Secondary literature sources for IL1

The following references were automatically generated.

Lin H et al.
Cloning and characterization of IL-1HY2, a novel interleukin-1 family member.
J Biol Chem. 2001; 276: 20597-602
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The interleukin-1 (IL-1) family members play an important role in the process of inflammation and host defense. We describe here the identification and characterization of a novel member of the IL-1 family, IL-1HY2. The human IL-1HY2 protein shares significant amino acid sequence similarity (37%) with the IL-1 receptor antagonist and has a predicted three-dimensional structure similar to that of the IL-1 receptor antagonist. The IL-1HY2 gene is located in close proximity to other IL-1 family genes on human chromosome 2, and the genomic organization of the IL-1HY2 gene is highly conserved with other IL-1 family members. IL-1HY2 protein is secreted from mammalian cells, and the purified recombinant IL-1HY2 protein binds soluble IL-1 receptor type I. IL-1HY2 is expressed in human skin, spleen, and tonsil. Immunohistochemical analysis showed that the IL-1HY2 protein is expressed in the basal epithelia of skin and in proliferating B cells of the tonsil. These data suggest that IL-1HY2 is a novel IL-1 family member and that it may participate in a network of IL-1 family members to regulate adapted and innate immune responses.

Long CS
The role of interleukin-1 in the failing heart.
Heart Fail Rev. 2001; 6: 81-94
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The prevalence of congestive heart failure and its continued poor prognosis despite presently available therapeutic options emphasize the importance of pursuing the observations suggesting an important role for an immunomodulatory approach to decompensated cardiac failure. Furthermore, there are several pieces of background information that suggest that cytokines like IL-1 may play a significant role in the pathogenesis of several forms of myocardial dysfunction. Although it seems clear that IL-1 is not acting alone under circumstances of myocardial injury, but in concert with other pro-inflammatory molecules and their effectors, we believe that continued investigations into the cytokine hypothesis will ultimately increase the understanding of how pro-inflammatory molecules influence myocardial function and how the modulation of such factors may improve the myocardial response to injury. The specific observations that emphasize the importance of pursuing a substantive role for IL-1 in this process are: (1) IL-1 is elevated in several cardiac disease states, (2) IL-1 is produced by myocardial cells themselves in response to injury, (3)The alterations in gene expression seen in response IL-1 resembles in many ways the phenotype of the failing heart, and (4) The co-localization of the IL-1 response with that of several previously described negative transcriptional regulators (making them potential targets for therapeutic manipulation).

Boch JA, Wara-aswapati N, Auron PE
Interleukin 1 signal transduction--current concepts and relevance to periodontitis.
J Dent Res. 2001; 80: 400-7
Display abstract
This review examines a well-characterized factor, interleukin 1 (IL-1), that has recently received considerable attention. A level of understanding is emerging that goes beyond simple recognition that IL-1 plays a role in disease, and begins to explain the molecular mechanisms of function. This review summarizes some current information on the importance of IL-1 in periodontitis as well as the signal transduction of IL-1, from binding to its cell-surface receptors, to the activation of cytoplasmic mediators and transcription factors responsible for the induction of target genes. The effect of IL-1 signal transduction is ultimately the activation and repression of specific transcription factors that regulate genes responsible for cellular activities. As additional steps of signal transduction become better-characterized, these insights may facilitate the development of improved therapeutic approaches for controlling inflammation and connective tissue destruction in a variety of diseases.

Mao XQ et al.
Imbalance production between interleukin-1beta (IL-1beta) and IL-1 receptor antagonist (IL-1Ra) in bronchial asthma.
Biochem Biophys Res Commun. 2000; 276: 607-12
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Genes of the IL-1 family encode three different peptides, IL-1alpha, IL-1beta, and IL-1Ra, respectively. IL-1 operates through IL-1RI, and is involved in airway inflammation in asthmatic subjects, whereas IL-1Ra appears to be a specific competitive inhibitor of IL-1. All genes are on chromosome 2q12-21 where genomewide searches have identified linkage for asthma. To test whether variants of IL-1 relate to asthma, we conducted a genetic association study in a Japanese population. We show that the A2 allele of IL1RN (encoding IL-1Ra) associates with nonatopic asthma [OR = 5.71, 95% CI: 1.63-19. 8, Pc = 0.007]. Both atopic and nonatopic asthmatics with the A2 allele had significantly lower serum IL-1Ra levels in both types of asthmatics. Peripheral blood cells from asthmatics with A2 alleles, however, produced as much IL-1 as did those with A1 homozygotes. Since Th1 and Th2 cytokines differentially regulate the ratio between IL-1beta and IL-1Ra, these findings suggest that dysregulation of IL-1beta/IL-1Ra, probably due to interaction between epithelium and immuno-competent cells in the airway, is important in asthma inflammation.

Sims JE
CDw121b.
J Biol Regul Homeost Agents. 2000; 14: 136-8

Smith DE, Renshaw BR, Ketchem RR, Kubin M, Garka KE, Sims JE
Four new members expand the interleukin-1 superfamily.
J Biol Chem. 2000; 275: 1169-75
Display abstract
We report here the cloning and characterization of four new members of the interleukin-1 (IL-1) family (FIL1delta, FIL1epsilon, FIL1zeta, and FIL1eta, with FIL1 standing for "Family of IL-1"). The novel genes demonstrate significant sequence similarity to IL-1alpha, IL-1beta, IL-1ra, and IL-18, and in addition maintain a conserved exon-intron arrangement that is shared with the previously known members of the family. Protein structure modeling also suggests that the FIL1 genes are related to IL-1beta and IL-1ra. The novel genes form a cluster with the IL-1s on the long arm of human chromosome 2.

Nalivaeva NN, Rybakina EG, Pivanovich IYu, Kozinets IA, Shanin SN, Bartfai T
Activation of neutral sphingomyelinase by IL-1beta requires the type 1 interleukin 1 receptor.
Cytokine. 2000; 12: 229-32
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The cytokine interleukin 1beta (IL-1beta) plays an important role in host defence reactions and neuro-immune interactions but it is still not clear which of the two interleukin 1 receptor subtypes is coupled to activation of neutral sphingomyelinase (nSMase) by IL-1beta. To investigate involvement of neutral sphingomyelinase (nSMase) in central IL-1beta effects we used P(2)fractions of brain cerebral cortex from wild-type mice and mice deficient in the type 1 IL-1 receptor. IL-1beta (human, recombinant) was shown to activate, in a dose-dependent manner, nSMase in the P(2)brain fraction of the wild-type mice while in the knock-out mice the stimulatory effect of IL-1beta on nSMase was absent. In the presence of an IL-1 receptor antagonist (IL-1ra), IL-1beta did not activate nSMase either in the cortex of wild-type or knock-out mice. These data suggest that nSMase, a key enzyme of the sphingomyelin signal transduction pathway, might be involved in IL-1beta signalling in the brain and that activation of the enzyme requires the IL-1 receptor type 1.

Rothwell NJ, Luheshi GN
Interleukin 1 in the brain: biology, pathology and therapeutic target.
Trends Neurosci. 2000; 23: 618-25
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The cytokine interleukin 1 (IL-1) has diverse actions in the brain. In normal brain the IL-1 system is expressed at low levels and is upregulated rapidly in response to local or peripheral insults. IL-1 mediates host defence responses to local and systemic disease and injury (e.g. fever, slow-wave sleep, appetite suppression and neuroendocrine responses) and to neuroinflammation and cell death in neurodegenerative conditions, such as stroke and head injury. It has also been implicated in chronic degenerative diseases, in particular, multiple sclerosis, Parkinson's and Alzheimer's diseases. The mechanisms regulating the expression and action of IL-1 are poorly understood, but involve multiple effects on neuronal, glial and endothelial cell function. Thus, the IL-1 system provides an attractive and intensely competitive target for therapeutic intervention.

Juffermans NP et al.
Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis.
J Infect Dis. 2000; 182: 902-8
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Interleukin (IL)-1 signaling is required for the containment of infections with intracellular microorganisms, such as Listeria monocytogenes and Leishmania major. To determine the role of IL-1 in the host response to tuberculosis, we infected IL-1 type I receptor-deficient (IL-1R(-/-)) mice, in which IL-1 does not exert effects, with Mycobacterium tuberculosis. IL-1R(-/-) mice were more susceptible to pulmonary tuberculosis, as reflected by an increased mortality and an enhanced mycobacterial outgrowth in lungs and distant organs, which was associated with defective granuloma formation, containing fewer macrophages and fewer lymphocytes, whereas granulocytes were abundant. Lymphocytes were predominantly confined to perivascular areas, suggesting a defective migration of cells into inflamed tissue in the absence of IL-1 signaling. Impaired host defense in IL-1R(-/-) mice was further characterized by a decrease in the ability of splenocytes to produce interferon-gamma. Analysis of these data suggests that IL-1 plays an important role in the immune response to M. tuberculosis.

Niimi T et al.
Lack of association with interleukin 1 receptor antagonist and interleukin-1beta gene polymorphisms in sarcoidosis patients.
Respir Med. 2000; 94: 1038-42
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Interleukin-1beta (IL-1beta) and its endogenous antagonist, the interleukin-1 receptor antagonist (IL-1ra), play important roles in immune responses. In sarcoidosis, IL-1beta is reported to be increased whereas IL-1ra is decreased. It has recently been shown that polymorphisms in the IL-1ra and IL-1beta genes may account for variation in the two proteins. These polymorphisms are also reported to be associated with several autoimmune diseases. Since this might be expected to affect sarcoidosis, an investigation of 108 sarcoidosis patients and 113 healthy control subjects was performed. The IL-1ra genotype was determined using the polymerase chain reaction (PCR), and the IL-1beta genotype by PCR restriction fragment length polymorphism. We found no significant differences in IL-ra and IL-1beta genotypes between sarcoidosis patients and healthy controls. Furthermore, there was no association between the IL-1beta genotype and the roentgenographic stage, disappearance of chest X-ray shadows or organ involvement. In conclusion, there is no bias in the IL-1ra and IL-1beta genotype in Japanese sarcoidosis patients.

Kollewe C, Neumann D, Martin MU
The first two N-terminal immunoglobulin-like domains of soluble human IL-1 receptor type II are sufficient to bind and neutralize IL-1beta.
FEBS Lett. 2000; 487: 189-93
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Two forms of soluble human type II interleukin (IL)-1 receptor (shIL-1RII) were generated, one consisting of the complete extracellular three immunoglobulin (Ig)-like domains and one containing only the first two N-terminal Ig-like domains. Both forms bound IL-1beta with a dissociation constant (K(d)) of 200 pM and neutralized IL-1beta in a bioassay. They did not bind or neutralize IL-1alpha. This demonstrates that the two Ig-like domains of shIL-1RII are sufficient to bind IL-1beta with an affinity comparable to full length shIL-1RII. This suggests that this short form of shIL-1RII contributes to the anti-inflammatory effect of soluble IL-1 receptors in vivo.

Attur MG et al.
Reversal of autocrine and paracrine effects of interleukin 1 (IL-1) in human arthritis by type II IL-1 decoy receptor. Potential for pharmacological intervention.
J Biol Chem. 2000; 275: 40307-15
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Interleukin 1 (IL-1), produced by both synovial cells and chondrocytes, plays a pivotal role in the pathogenesis of cartilage destruction in osteoarthritis (OA). We examined the specific expression and function of IL-1 receptor family-related genes in human joint tissues. Gene array analysis of human normal and OA-affected cartilage showed mRNA expression of IL-1 receptor accessory protein (IL-1RAcp) and IL-1 type I receptor (IL-1RI), but not IL-1 antagonist (IL-1ra) and IL-1 type II decoy receptor (IL-1RII). Similarly, human synovial and epithelial cells showed an absence of IL-1RII mRNA. Functional genomic analyses showed that soluble (s) IL-1RII, at picomolar concentrations, but not soluble TNF receptor:Fc, significantly inhibited IL-1beta-induced nitric oxide (NO) and/or prostaglandin E(2) production in chondrocytes, synovial and epithelial cells. In OA-affected cartilage, the IC(50) for inhibition of NO production by sIL-1RII was 2 log orders lower than that for sIL-1RI. Human chondrocytes that overexpressed IL-1RII were resistant to IL-1-induced IL-1beta mRNA accumulation and inhibition of proteoglycan synthesis. In osteoarthritis, deficient expression by chondrocytes of innate regulators or antagonists of IL-1 such as IL-1ra and IL-1RII (soluble or membrane form) may allow the catabolic effects of IL-1 to proceed unopposed. The sensitivity of IL-1 action to inhibition by sIL-1RII has therapeutic implications that could be directed toward correcting this unfavorable tissue(s) dependent imbalance.

Moos V, Rudwaleit M, Herzog V, Hohlig K, Sieper J, Muller B
Association of genotypes affecting the expression of interleukin-1beta or interleukin-1 receptor antagonist with osteoarthritis.
Arthritis Rheum. 2000; 43: 2417-22
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OBJECTIVE: The majority of cytokines and growth factors known to be involved in cartilage metabolism are synthesized by the chondrocytes themselves. They are up-regulated in osteoarthritic (OA) cartilage, resulting in 2 opposite phenotypes, TNFalpha(high) and TNFalpha(low), that are characterized by an elevated number of tumor necrosis factor alpha (TNFalpha)-positive and interleukin-1beta (IL-1beta)-positive chondrocytes, respectively. To establish a hierarchy among the cytokines and growth factors expressed in articular chondrocytes, this study investigated cytokine genes for known polymorphisms that may contribute to the deregulated expression in OA cartilage. METHODS: Polymerase chain reaction techniques were performed either in a thermal cycler using standard methods or in a light cycler to analyze the frequencies of the TNFalpha (-308), IL-1 receptor antagonist (IL-1Ra) (intron 2), IL-1beta (exon 5), and IL-6 (-174) polymorphisms in 61 OA patients and 254 randomly chosen controls. RESULTS: For the TNFalpha(low) phenotype, a statistically significant association was found with the less frequent allele of IL-1beta, which carries a single-basepair substitution in exon 5 and may contribute to the characteristic increase in IL-beta-positive chondrocytes. In contrast, the TNFalpha(high) phenotype was significantly associated with the less frequent allele of IL-1Ra, which carries two 86-bp repeats in the second intron and is assumed to lead to an elevated expression of the antagonist. CONCLUSION: These results point to an association between the IL-1beta polymorphism and the TNFalpha(high) phenotype and between the IL-1Ra polymorphism and the TNFalpha(low) phenotype found in OA. Both associations suggest that IL-1beta may be more important than TNFalpha for the regulation of cytokine and growth factor expression in articular chondrocytes.

Daig R et al.
Human intestinal epithelial cells secrete interleukin-1 receptor antagonist and interleukin-8 but not interleukin-1 or interleukin-6.
Gut. 2000; 46: 350-8
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BACKGROUND: There is growing evidence that intestinal epithelial cells (IECs) are involved in the mucosal immune system. AIM: To assess the pattern of cytokines secreted by IECs and lamina propria mononuclear cells (LPMNCs). To achieve this, the expression and secretion of interleukin (IL)-1, IL-1 receptor antagonist (IL-1ra), IL-6, and IL-8 in human primary colonic and ileal IECs and LPMNCs from the same patient were studied. METHODS: IECs and LPMNCs were isolated from surgical specimens or endoscopic biopsy samples. mRNA expression was investigated by northern blot analysis. Secretion of IL-1beta, IL-6, IL-8, and IL-1ra was measured by enzyme linked immunosorbent assay. RESULTS: IL-1ra mRNA levels were higher in IECs than in LPMNCs in all probands. IL-8 mRNA was only present in low amounts in the IECs from two controls. In none of the specimens were IL-1beta and IL-6 mRNA present in IECs. Transcripts encoding IL-1beta, IL-1ra, IL-6, and IL-8 were identified in LPMNC preparations of all specimens. IECs from normal mucosa produced no detectable amounts of IL-1beta or IL-6, whereas LPMNCs did. IECs secreted some IL-8 (65 (9) pg/10(5) cells) but significantly more was generated by LPMNCs (408 (43) pg/10(5) cells, p<0.0001). However, IECs secreted more IL-1ra than did LPMNCs (120 (12) v 94 (11) pg/10(5) cells). In acute inflammation, IEC IL-1ra secretion was significantly increased. A correlation between secreted IL-1ra and the macroscopical degree of inflammation was found in Crohn's disease (r = 0.64, p<0.0001, n = 36) and ulcerative colitis (r = 0. 76, p<0.0001, n = 24). CONCLUSIONS: IECs from normal mucosa express and secrete IL-1ra and low amounts of IL-8, but no IL-1 or IL-6. In inflamed mucosa the secretion of IL-1ra by IECs is slightly increased but may be not sufficient to antagonise the greatly increased production of proinflammatory cytokines by LPMNCs and the IECs themselves.

Gabay C
[Interleukin-1 inhibitors: a new alternative for the treatment of rheumatoid polyarthritis]
Rev Med Suisse Romande. 2000; 120: 529-33

Orlando S, Polentarutti N, Mantovani A
Selectivity release of the type II decoy IL-1 receptor.
Cytokine. 2000; 12: 1001-6
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The type II IL-1 receptor (IL-1RII) is a non-signalling molecule which acts as a decoy target for IL-1. Various signals (e.g. chemoattractants and phorbol ester) induce metalloprotease-mediated rapid shedding of the IL-1RII. The present study was designed to compare the susceptibility to shedding of the decoy IL-1RII vs the signalling IL-1RI. HEK 293 cells and COS cells were transfected with cDNAs encoding the human IL-1RI, IL-1RII or both. Slow spontaneous release and rapid phorbol ester-induced shedding were only observed for the decoy IL-1RII. Similarly, OVCAR-3 cells, which express substantial amounts of both IL-1RI and IL-1RII, only released the IL-1RII. These results indicate that the IL-RII, but not the IL-1RI, is susceptible to proteolytic shedding, a finding consistent with the decoy function of this molecule.

Dinarello CA
The role of the interleukin-1-receptor antagonist in blocking inflammation mediated by interleukin-1.
N Engl J Med. 2000; 343: 732-4

Barton JL, Herbst R, Bosisio D, Higgins L, Nicklin MJ
A tissue specific IL-1 receptor antagonist homolog from the IL-1 cluster lacks IL-1, IL-1ra, IL-18 and IL-18 antagonist activities.
Eur J Immunol. 2000; 30: 3299-308
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Interleukin (IL)-1-like protein 1 (IL-1L1) is a 155-amino acid protein that shares 27% identity with IL-1beta and 47% with IL-1 receptor antagonist (IL-1ra). A 2.7-kb IL-1L1 mRNA was cloned from human placenta and is detectable in the trophoblastic cell line JEG-3, in macrophages and in endotoxin-stimulated monocytes. Expression of IL-1L1 is much less abundant and less widespread than IL-1ra. We have determined the human and mouse IL-1L1 cDNA sequences and the complete sequence of the human gene, IL1L1. IL1L1 consists of four coding exons, has two alternative non-coding first exons, lies between IL1B and IL1RN, is orientated in the same direction as IL1RN and is separated from it by approximately 53 kb. The predicted IL-1L1 protein lacks both signal sequence and glycosylation signals. A 17-kDa protein was recovered by immunoprecipitation with IL-1L1-specific antibodies from JEG-3. IL-1L1 did not stimulate IL-6 production from primary human fibroblasts or human umbilical vein endothelial cells nor did it block the IL-1alpha or IL-1beta-dependent activation of IL-6 expression. We conclude, contrary to a recent suggestion made by others, that IL-1L1 is not a functional IL-1ra. IL-1L1 also had no detectable agonistic or antagonistic effect on IFN-gamma production in response to IL-18 in KG-1 cells.

Konsman JP, Blond D, Vigues S
Neurobiology of interleukin-1 receptors: getting the message.
Eur Cytokine Netw. 2000; 11: 699-702
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Binding of the pro-inflammatory cytokine interleukin-1 (IL-1) in the brain was first shown a decade ago [1]. Interleukin-1 receptors (IL-1R) in the brain were, at that time, proposed to play a role in mediating symptoms of sickness such as fever, activation of the hypothalamo-pituitary adrenal (HPA)-axis, behavioural depression and increased sleeping. Two years later, IL-1 immunoreactivity was shown in microglia of patients with Alzheimer's disease [2]. Subsequent studies provided evidence for IL-1 expression in most acute and chronic CNS pathologies and gave rise to the concept that glial IL-1 contributes to an inflammatory response in the brain. Recently, new members of the IL-1 receptor family have been discovered and roles for brain IL-1 other than in inflammation are starting to emerge. During a recent meeting* in Biarritz, leading experts in the field reflected on the accomplishments and prospects in this rapidly expanding area of neurobiology.

Knoblach SM, Faden AI
Cortical interleukin-1 beta elevation after traumatic brain injury in the rat: no effect of two selective antagonists on motor recovery.
Neurosci Lett. 2000; 289: 5-8
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Interleukin-1 is an inflammatory cytokine implicated in secondary responses to traumatic brain injury. We utilized a specific IL-beta enzyme-linked immunoadsorbant assay to examine the expression of IL-beta after lateral fluid percussion brain injury in the rat. IL-beta was significantly elevated in the ipsilateral injured cortex at 4 h after injury. Increased levels of IL-beta were also observed at 12, 24 and 72 h after injury, although such changes did not reach statistical significance. To determine whether injury-induced IL-beta expression may contribute to subsequent neurological impairment, we treated rats with either of two structurally different, selective IL-1 antagonists and monitored neurological recovery 1, 7 and 14 days later. Intracerebroventricular treatment with either the endogenous interleukin-1 receptor antagonist (10 microg) at 15 min, 2, 4, 6, and 8 h after injury or soluble IL-1 receptors (10 microg) at 15 min, 4 and 8 h after injury did not significantly alter outcome in a series of motor tasks. These data suggest that cortical elevations of IL-beta follow traumatic brain injury, but they may not contribute to subsequent neurological impairment.

Ilyin SE, Gonzalez-Gomez I, Romanovicht A, Gayle D, Gilles FH, Plata-Salaman CR
Autoregulation of the interleukin-1 system and cytokine-cytokine interactions in primary human astrocytoma cells.
Brain Res Bull. 2000; 51: 29-34
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Cytokines are proposed to play important roles in brain tumor biology. Previous studies reported on interleukin-1beta (IL-1beta) production and IL-1 receptor type I (IL-1RI, signaling receptor) expression in human astrocytomas, and on IL-1beta action in astrocytoma cell lines. However, all studies that have tested the direct action of cytokines have used exclusively astrocytoma cell lines, which do not recapitulate the in situ astrocytoma. Here, we demonstrate that astrocytoma cells obtained shortly after tumor neurosurgical resection respond to the direct application of human IL-1beta with a significant upregulation of IL-1alpha, IL-1beta, IL-1RI, and tumor necrosis factor-alpha (TNF-alpha) mRNAs. IL-1 receptor antagonist (IL-1Ra, an endogenous inhibitor that blocks IL-1alpha and IL-1beta actions) mRNA was not upregulated. Application of heat-inactivated IL-1beta had no effect on any cytokine component examined, demonstrating specificity of action. On the other hand, IL-1beta application did not modulate any cytokine component in acutely resected and dissociated primitive neuroectodermal tumor cells. The data have implications for a positive autoregulatory IL-1beta feedback system and synergistic IL-1beta <=> TNF-alpha interactions, which can be involved in the growth of pilocytic astrocytomas. The results together with our previous studies also support the notion that IL-1Ra or a compound with similar cytokine inhibitory activity could be useful for brain immunotherapy of astrocytomas.

Laurincova B
Interleukin-1 family: from genes to human disease.
Acta Univ Palacki Olomuc Fac Med. 2000; 143: 19-29
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Interleukin-1 (IL-1) is one of the most potent proinflammatory cytokines involved both in physiological immune responses and in the development of various immunopathological disorders. The members of IL-1 family form a complex system with tight regulatory mechanisms and clarifying their role in disease remains in the centre of research interests. This review article except of summarising recent findings about IL-1 family members focuses on associations of IL-1 gene complex polymorphisms with human diseases.

Soder O, Sultana T, Jonsson C, Wahlgren A, Petersen C, Holst M
The interleukin-1 system in the testis.
Andrologia. 2000; 32: 52-5
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The interleukin-1 (IL-1) family consists of two agonist proteins, IL-1 alpha and IL-1 beta, and one antagonist, IL-1 receptor antagonist (IL-1ra), which blocks the action of the agonists by binding and competing at the IL-1 receptor level. IL-1 beta and to a lesser extent IL-1 alpha were originally described as rapidly inducible proinflammatory cytokines released by activated macrophages. However, IL-1 alpha has been found to be constitutively produced by certain tissues, and noninflammatory functions have been proposed for this protein, although they have not yet been well elucidated. Consistent with this suggestion, we previously showed that the intact rat testis constitutively produces large amounts of IL-1 alpha at both the mRNA and protein levels. The expression of IL-1 alpha was found to be confined to Sertoli cells, with evidence of a developmental as well as a stage-dependent production pattern. In more recent studies, we have found indications that the testis can also initiate production of IL-1 beta upon stimulation with inflammatory inducers such as endotoxin. Further, we have detected constitutive testicular expression of IL-1ra, opening up the possibility that IL-1 action in the testis may be specifically regulated by paracrine mechanisms. Recent data have demonstrated that the testis can produce more than one isoform of IL-1 alpha with indications of both post-transcriptional and post-translational modifications, resulting in at least three distinct bio- and immunoreactive IL-1 alpha proteins. We conclude that all three classical IL-1 ligands and novel IL-1 alpha isoforms are present in the testis and may serve as paracrine mediators under physiological or pathophysiological conditions. The function of this testicular IL-1 agonist-antagonist network is a current focus of investigation.

Beck G, Ellis TW, Truong N
Characterization of an IL-1 receptor from Asterias forbesi coelomocytes.
Cell Immunol. 2000; 203: 66-73
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The tremendous importance of cytokines to immune defensive systems suggests that they have been conserved through evolution. The existence of interleukin (IL)-1-like molecules in several invertebrate groups substantiates this hypothesis. To characterize further the relationship of invertebrate IL-1-like molecules, we have used competitive binding assays to show that invertebrate coelomocytes of the starfish Asterias forbesi possess an IL-1-specific binding protein. Competitive binding experiments used radiolabeled human IL-1alpha. IL-1 bound specifically to the coelomocytes by a single high-affinity binding site (K(d) = 8.72 x 10(-10)/M). There are approximately 6000 binding sites per cell. The specificity of the receptor was confirmed by demonstrating that, among a group of cytokines and lymphokines tested, only vertebrate IL-1- or echinoderm IL-1-like molecules and the vertebrate IL-1 receptor antagonist inhibit IL-1 binding. Treatment of coelomocytes (labeled with IL-1alpha) with bivalent water-soluble crosslinkers identified a membrane protein of approximately 70 kDa to which IL-1 is specifically crosslinked.

Nashan D, Luger TA
[Interleukin 1. 1: Basic principles and pathophysiology]
Hautarzt. 1999; 50: 680-8

Touzani O, Boutin H, Chuquet J, Rothwell N
Potential mechanisms of interleukin-1 involvement in cerebral ischaemia.
J Neuroimmunol. 1999; 100: 203-15
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Interleukin-1 (IL-1) has pleiotropic actions in the central nervous system. During the last decade, a growing corpus of evidence has indicated an important role of this cytokine in the development of brain damage following cerebral ischaemia. The expression of IL-1 in the brain is dramatically increased during the early and chronic stage of infarction. The most direct evidence that IL-1 contributes significantly to ischaemic injury is that (1) central administration of IL-1beta exacerbates brain damage, and (2) injection or over-expression of interleukin-1 receptor antagonist, and blockade of interleukin-1beta converting enzyme activity reduce, dramatically, infarction and improve behavioural deficit. The mechanisms underlying IL-1 actions in stroke are not definitively elucidated, and it seems likely that its effects are mediated through stimulation and inhibition of wide range of pathophysiological processes.

Kol S et al.
The rat intraovarian interleukin (IL)-1 system: cellular localization, cyclic variation and hormonal regulation of IL-1beta and of the type I and type II IL-1 receptors.
Mol Cell Endocrinol. 1999; 149: 115-28
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An increasing body of evidence supports the possibility that intraovarian interleukin (IL)-1 plays an intermediary role in the periovulatory cascade. To gain further insight into the intraovarian IL-1 hypothesis, we studied the cellular localization cyclic variation and hormonal regulation of IL-1beta, as well as of the type I and type II IL-1 receptors (IL-1R) in immature rats. In situ hybridization localized IL-1beta and type I IL-1R transcripts to the granulosa cell compartment, the innermost layers of the theca interna and to the oocyte of the untreated immature ovary. Molecular probing of whole ovarian material in the course of a simulated estrous cycle revealed a progressive preovulatory increase in IL-1beta and type I IL-1R transcripts to an in vivo peak at the time of ovulation (3.0- and 2.5-fold increases over untreated controls; P < 0.05). Comparable efforts to localize and probe for type II IL-IR transcripts failed to elicit a detectable signal. The basal in vitro expression pattern of IL-1beta and type II IL-1R transcripts by whole ovarian dispersates revealed an early (4 h) spontaneous increase to a peak (2.1- and 5.8-fold increases over time 0: P < 0.05) followed by a gradual decline to a 48 h nadir. Treatment of whole ovarian dispersates with the IL-1 receptor antagonist (IL-1RA) or with IL-1beta failed to alter the initial (4 h) burst of IL-1beta or of type II IL-1R expression thereby suggesting IL-1-independence. Treatment with hCG proved equally ineffective. However, longer-term treatment of whole ovarian dispersates with IL-1beta produced a significant secondary increase (5.9-fold over time 0; P < 0.05) in IL-1beta (but not type II IL-1R) transcripts by 48 h. This IL-1 effect was completely blocked by co-treatment with IL-1RA thereby suggesting mediation via a specific IL-1 receptor. Qualitatively comparable but quantitatively reduced results obtained for isolated granulosa cells. The basal in vitro expression pattern of type I IL-1R transcripts by whole ovarian dispersates revealed a progressive spontaneous increase (3.1-fold increase overall) over the 48 h culture. Treatment with IL-1beta produced a significant (P < 0.05) increase (5-fold) in type I IL-1R transcripts by 48 h, an effect which was completely blocked by co-treatment with IL-1RA. Taken together, these observations: (1) localize IL-1beta and its type I receptor to granulosa cells, the innermost layers of the theca interna and to the oocyte; (2) confirm their periovulatory in vivo expression pattern; (3) document their expression by untreated cultured whole ovarian dispersates; and (4) demonstrate their in vitro responsiveness to receptor-mediated/IL-1-driven autocrine amplification. The type II IL-1R was undetectable in vivo, its in vitro expression pattern proving IL-1- and hCG-independent. The periovulatory expression pattern of IL-1beta and its receptor (type I) is compatible with the notion that the intraovarian IL-1 system may play an intermediary role in the ovulatory process.

Tadano T et al.
Induction of nociceptive responses by intrathecal injection of interleukin-1 in mice.
Life Sci. 1999; 65: 255-61
Display abstract
Intrathecal (i.t.) injection (between lumbar vertebrae 5 and 6) into mice of a markedly low dose of IL-1alpha (3x10(-4) fmol or 5.4 fg in 5 microl per mouse) induced behaviors involving scratching, biting, and licking of non-stimulated hindpaws. The IL-1-induced behaviors appeared within 10 min of the injection of IL-1alpha, peaked at 20-40 min, and had disappeared 60 min after the injection. The IL-1-induced behaviors were similar to the nociceptive responses induced in mice by i.t. injection of substance P (SP) or subcutaneous (s.c.) injection of formalin into the footpad. The IL-1-induced behaviors were suppressed by intraperitoneal morphine, indicating that they are nociceptive responses. The nociceptive responses induced by 3x10(-4) (5.4 fg) of IL-1alpha were almost completely suppressed by co-injection of 0.3 fmol (7.2 pg) of an IL-1 receptor antagonist (IL-1ra). An antiserum against substance P, but not an antiserum against somatostatin, suppressed the IL-1-induced nociceptive responses. The nociceptive responses induced by s.c. injection of 2% formalin into the footpad were also inhibited by i.t. injection of 30 pmol (720 ng) of IL-1ra. These results suggest that IL-1 may play a role in hyperalgesia in mice by acting as a factor augmenting pain transmission in the spinal cord at least in part by either directly or indirectly releasing substance P.

Carlson NG, Wieggel WA, Chen J, Bacchi A, Rogers SW, Gahring LC
Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways.
J Immunol. 1999; 163: 3963-8
Display abstract
The proinflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha are produced within the CNS, and, similar to the periphery, they have pleotrophic and overlapping functions. We have shown previously that TNF-alpha increases neuronal survival to a toxic influx of calcium mediated through neuronal N-methyl-d -aspartic acid (NMDA) glutamate-gated ion channels. This process, termed excitotoxicity, is a major contributor to neuronal death following ischemia or stroke. Neuroprotection by this cytokine requires both activation of the p55/TNF receptor type I and the release of TNF-alpha from neurons, and it is inhibited by the plant alkaloid nicotine. Here, we report that other inflammatory cytokines (IL-1 alpha, IL-1 beta, and IL-6) are also neuroprotective to excessive NMDA challenge in our system. Neuroprotection provided by IL-1 is distinct from TNF-alpha because it is inhibited by IL-1 receptor antagonist; it is not antagonized by nicotine, but it is inhibited by a neutralizing Ab to nerve growth factor (NGF). Similar to IL-1, IL-6-mediated neuroprotection is also antagonized by pretreatment with IL-1 receptor antagonist and it is not affected by nicotine. However, neutralizing anti-NGF only partially blocks IL-6-mediated protection. These studies support an important role for distinct but overlapping neuroprotective cytokine effects in the CNS.

Kol S, Wong KH, Ando M, Ben-Shlomo I, Adashi EY
Rat ovarian interleukin-1alpha: interleukin-1-dependent in vitro expression.
Endocrine. 1999; 11: 269-75
Display abstract
Evidence exists supporting the possibility that intraovarian interleukin-1 (IL-1) may play an intermediary role in the periovulatory cascade. Although the existence of a mammalian intraovarian IL-1 system has been convincingly demonstrated, most efforts have focused on the possibility that the mammalian ovary is a site of IL-1b production, reception, and action. The objective of this study was to explore the possibility of ovarian IL-1a expression, characterize its pattern of expression by cultured ovarian cells, and study its hormonal regulation. The basal in vitro expression of IL-1a by cultured whole ovarian dispersates from immature rats increased spontaneously, reaching a peak (sixfold increase over untreated controls) at 4 h. Treatment with an IL-1 receptor antagonist (IL-1RA), human chorionic gonadorropin, or IL-1b failed to attenuate the initial 4-h burst of IL-1a expression. By contrast, treatment of whole ovarian dispersates with IL-1b for 48 h resulted in significant upregulation of IL-1a transcripts (60-fold increase). This IL-1b effect was completely blocked by cotreatment with IL-1RA, thereby suggesting mediation via a specific IL-1 receptor. The IL-1b effect proved to be protein biosynthesis and eicosanoid dependent, nitric oxide independent, and relatively specific in that it was not reproduced by a select series of other granulosa cell agonists.

Watkins LR, Hansen MK, Nguyen KT, Lee JE, Maier SF
Dynamic regulation of the proinflammatory cytokine, interleukin-1beta: molecular biology for non-molecular biologists.
Life Sci. 1999; 65: 449-81
Display abstract
Interleukin-1beta (IL-1beta) is a key mediator and modulator of a wide array of physiological responses important for survival. It is created by a variety of cell types, including immune cells, glia, and neurons. It is a very potent biological molecule, acting both at the periphery as well as within the central nervous system. The production and release of IL-1beta is tightly regulated by far more complex processes than previously thought. An appreciation of this complexity is necessary for proper interpretation of apparent contradictions in the literature where different aspects of IL-1beta expression are measured. Given that many researchers are not molecular biologists by training, yet need an appreciation of the controls that regulate the function of key proteins such as IL-1beta, this review is aimed at both: (a) clarifying the multiple levels at which IL-1beta production is modulated and (b) using IL-1beta regulation to explain the dynamics of gene regulation to non-molecular biologists. Three major topics will be discussed. First, regulation of IL-1beta production will be examined at every level from extracellular signals that trigger gene activation through release of active protein into the extracellular fluid. Second, regulation of IL-1beta bioavailability and bioactivity will be discussed. This section examines the fact that even after IL-1beta is released, it may or may not be able to exert a biological action due to multiple modulatory factors. Last is the introduction of the idea that IL-1beta regulation is, at times, beyond the direct control of host; that is, when IL-1beta production becomes dysregulated by pathogens.

Cooper AL, Beasley D
Hypoxia stimulates proliferation and interleukin-1alpha production in human vascular smooth muscle cells.
Am J Physiol. 1999; 277: 132637-132637
Display abstract
Several lines of evidence indicate that hypoxia is a stimulus to vascular smooth muscle cell (VSMC) proliferation that occurs in pulmonary hypertension. The present study tested the hypothesis that low O(2) tension directly stimulates human VSMC proliferation by inducing them to produce interleukin (IL)-1, a potent autocrine growth factor for human VSMC. Human VSMC derived from pulmonary artery, aorta, or saphenous vein were incubated in either a normal in vitro O(2) environment (20% O(2)) or in chambers containing low (approximately 1%) or moderate (5%) O(2). Levels of IL-1alpha and IL-1beta mRNA increased in human VSMC after 24-48 h of incubation in low O(2) compared with levels in normoxic cells and then decreased upon subsequent reoxygenation. Levels of cell-associated IL-1alpha also increased progressively after 24-48 h in low O(2); however, detectable IL-1alpha was not released from the cells in the media. IL-1beta was detectable in cell lysates and supernatants; however, the levels were not affected by exposure to low O(2). mRNA encoding for tumor necrosis factor-alpha (TNF-alpha), a related cytokine and VSMC mitogen, was not detectable in human VSMC exposed to either low or 20% O(2). Proliferation of human VSMC was not stimulated during exposure to low O(2), despite the fact that cells remained responsive to the mitogenic effect of exogenous IL-1. Interestingly, however, exposure to 5% O(2) enhanced proliferation of human VSMC but did not induce IL-1alpha production. Inhibition of IL-1 binding to the type I IL-1 receptor by exogenous addition of IL-1-receptor antagonist (10 microgram/ml) did not attenuate the proliferation rates of human VSMC incubated in 20%, 5%, or low O(2) or in human VSMC that were reoxygenated after exposure to low O(2). These results demonstrate two direct and distinct effects of hypoxia on VSMC. Exposure to moderately low O(2) tension induces VSMC proliferation, independent of IL-1, whereas exposure to very low O(2) tension induces production of IL-1alpha.

Li X, Commane M, Burns C, Vithalani K, Cao Z, Stark GR
Mutant cells that do not respond to interleukin-1 (IL-1) reveal a novel role for IL-1 receptor-associated kinase.
Mol Cell Biol. 1999; 19: 4643-52
Display abstract
Mutagenized human 293 cells containing an interleukin-1 (IL-1)-regulated herpes thymidine kinase gene, selected in IL-1 and gancyclovir, have yielded many independent clones that are unresponsive to IL-1. The four clones analyzed here carry recessive mutations and represent three complementation groups. Mutant A in complementation group I1 lacks IL-1 receptor-associated kinase (IRAK), while the mutants in the other two groups are defective in unknown components that function upstream of IRAK. Expression of exogenous IRAK in I1A cells (I1A-IRAK) restores their responsiveness to IL-1. Neither NFkappaB nor Jun kinase is activated in IL-1-treated I1A cells, but these responses are restored in I1A-IRAK cells, indicating that IRAK is required for both. To address the role of the kinase activity of IRAK in IL-1 signaling, its ATP binding site was mutated (K239A), completely abolishing kinase activity. In transfected I1A cells, IRAK-K239A was still phosphorylated upon IL-1 stimulation and, surprisingly, still complemented all the defects in the mutant cells. Therefore, IRAK must be phosphorylated by a different kinase, and phospho-IRAK must play a role in IL-1-mediated signaling that does not require its kinase activity.

Bol GF, Tewes F, Brigelius-Flohe R
Interleukin-1 signaling is dependent on free thiols.
Biofactors. 1999; 10: 175-8
Display abstract
Stimulation of the Interleukin-1 receptor type I (IL-1-RI) with IL-1 activates an associated serine/threonine kinase, IRAK, which phosphorylates downstream targets, resulting in NFkappaB activation. The signaling cascade is accompanied by oxidative processes and contains putative targets for redox regulation. Preincubation of the murine T cell line EL-4 and the human umbilical cord vein endothelial cell line ECV 304 with thiol modifying compounds like diamide, menadione or phenylarsine oxide inhibited the IL-1-induced phosphorylation of an endogenous substrate with a molecular mass of 60 kD. In the endothelial cell line, a second target of about 85 kD was phosphorylated after IL-1 stimulation, which was also inhibited by thiol modification. These data suggest that IL-1 signal transduction depends on free thiols which might be targets for redox regulation not only in lymphocytes, but also in endothelial cells.

Arondel J, Singer M, Matsukawa A, Zychlinsky A, Sansonetti PJ
Increased interleukin-1 (IL-1) and imbalance between IL-1 and IL-1 receptor antagonist during acute inflammation in experimental Shigellosis.
Infect Immun. 1999; 67: 6056-66
Display abstract
Infection by the enteric bacterial pathogen Shigella results in intense mucosal inflammation and destruction of the colonic and rectal epithelium in infected humans. Initial bacterial translocation occurs through the follicle-associated epithelium. Previous experiments suggest that interleukin-1 (IL-1) is crucial to trigger inflammation, particularly in the follicular zones. During the first 4 hours of infection in a rabbit ligated-loop model of intestinal invasion, there are two salient characteristics: (i) a high concentration of IL-1alpha and IL-1beta, both in infected Peyer's patch tissue and in the corresponding efferent mesenteric blood, and (ii) a very low level of expression of IL-1 receptor antagonist (IL-1ra). These may reflect a combination of regulation of expression and secretion of IL-1alpha, IL-1beta, and IL-1ra by both resident and recruited phagocytes and the induction of mononuclear phagocyte apoptosis by Shigella. This low IL-1ra/IL-1 ratio likely accounts for the rapid, uncontrolled inflammation characteristic of shigellosis.

Gabellec MM, Crumeyrolle-Arias M, Le Saux F, Auriou N, Jacque C, Haour F
Expression of interleukin-1 genes and interleukin-1 receptors in the mouse brain after hippocampal injury.
Neurosci Res. 1999; 33: 251-60
Display abstract
In order to evaluate the role of IL-1 production in post-traumatic brain, transcripts for IL-1 (alpha, beta, RA) have been quantified following RT-PCR, in hippocampus and cortex after injury of either hippocampus (Hip) or striatum (Stri). Moreover, 125I IL-1alpha binding sites have been directly quantified using binding experiments on brain sections and quantitative autoradiography. Under basal conditions, levels of PCR products were very low. On day 1, IL-1RA transcripts only were strongly increased in the hippocampus after Hip-lesions and in cortex after Stri lesion. Transcripts were back to control values on day 7 post-lesion. IL-1 receptor densities in the hippocampus (dentate gyrus) were decreased at day 1 around the site of the lesion (but not on the contralateral side) and were back to controls on day 7 indicating a transient and local IL-1 production in the surroundings of the lesion. No changes were found following Stri lesion. This study provides further evidence of the role of the IL-1 molecules family, notably IL-1RA, in the brain reaction to trauma.

Krakauer T, Krakauer H
A method for correcting for the variability of inhibitory effects of soluble human interleukin 1 receptor II measured by different ELISAS.
J Immunoassay. 1999; 20: 185-200
Display abstract
Seven ELISAs were developed by using several combinations of anti-human IL-1beta antibodies for detecting interleukin 1beta (IL-1beta) in cell culture supernatants. These ELISAs have different sensitivities in detecting standard preparations of recombinant human IL-1beta (WHO reference standard) compared with conventional preparations of IL-1beta produced by stimulated human peripheral blood mononuclear cells. The observed differences were attributed to differences in epitope specificity of the various monoclonal antibodies used and the heterogeneity of IL-1beta secreted into culture supernatants. The presence of soluble IL-1 receptor type I did not alter the levels of IL-1beta detected by these ELISAs. However, soluble IL-1 receptor type II interfered with the detection of IL-1beta to different degrees in these ELISAs. A method involving standarization by means of separate measurement of the amount of receptor and its inhibitory effect in the IL-1beta ELISA, yields consistent estimates of the correct IL-1beta levels.

Dinarello CA
Is there an interleukin-1 genetic predisposition to developing severe sepsis?
Crit Care Med. 1999; 27: 1397-8

Nashan D, Luger TA
[Interleukin 1. Part 2: Mode of action and therapeutic possibilities]
Hautarzt. 1999; 50: 756-63

Schrijver HM et al.
Association of interleukin-1beta and interleukin-1 receptor antagonist genes with disease severity in MS.
Neurology. 1999; 52: 595-9
Display abstract
OBJECTIVE: To investigate whether polymorphisms in the interleukin (IL)-1beta and IL-1 receptor antagonist (IL-1RA) genes are associated with both susceptibility to and clinical characteristics of MS. BACKGROUND: Genetic susceptibility to MS is determined by many partially identified genes. The genes encoding various cytokines are logical candidates for MS susceptibility and phenotype. METHODS: Genotypes were determined from 148 patients with clinically definite MS and 98 healthy controls. All the patients were unrelated, Dutch, and white. Patient files were reviewed for disease type, initial symptoms, age at onset of disease, and rate of disease progression. RESULTS: No significant differences in genotypes, allele frequencies, or carrier frequencies were found between MS patients and healthy controls. Stratification for disease type (relapsing-remitting, primary progressive, or secondary progressive) did not provide significant differences between patients and controls. However, a specific IL-1RA/IL-1beta combination was associated with disease severity. MS patients with the IL-1RA allele 2+/IL-1beta allele 2- combination had a higher rate of progression on the Expanded Disability Status Scale when compared with the other possible combinations (p = 0.007). CONCLUSIONS: IL-1RA and IL-1beta are disease severity genes rather than disease susceptibility genes. Furthermore, these gene polymorphisms may define subgroups of patients with a worse prognosis.

Heal JR, Bino S, Ray KP, Christie G, Miller AD, Raynes JG
A search within the IL-1 type I receptor reveals a peptide with hydropathic complementarity to the IL-1beta trigger loop which binds to IL-1 and inhibits in vitro responses.
Mol Immunol. 1999; 36: 1141-8
Display abstract
In previous research, we were able to demonstrate that a seven amino acid residue peptide (VITFFSL), designed as an antisense peptide of the beta-bulge trigger loop region of interleukin 1beta (IL-1beta) (QGEESND; residues 48-54 [mature protein sequence]), was able to interact with IL-1 specifically and inhibit the response to IL-1 in an in vitro bioassay. The evidence was consistent with a specific interaction ocurring between antisense peptide and the trigger loop region. On the basis that antisense peptides are able to interact with their corresponding sense peptide sequences as a result of their mutually complementary hydropathic profiles (Fassina G., Verdoliva, A., Cassani, G., Melli, M., 1994. Binding of type I IL-1 receptor fragment 151-162 to IL-1. Growth Factors 10, 99-106; Maier, C.C., Moseley, H.N.B., Zhou, S., Whitaker, J.N., Blalock, J.E., 1994. Indentification of interactive determinants on idiotypic-anti-idiotypic antibodies through comparison of their hydropathic profiles. Immunomethods 5, 107-113), we devised a computer program (FINDH) to search the amino acid residue sequence of interleukin-1 type 1 receptor (IL-1 R1) for peptide motifs possessing hydropathic complementarity to the trigger loop sequence. The most complementary "best-fit peptide" motif (LITVLNI) was located in the third extracellular domain of IL-1 R1. A best-fit peptide corresponding to this motif was synthesised and found to bind to IL-1beta as well as inhibit the response to IL-1 in two independent in vitro bioassays (monitoring IL-1 dependent serum amyloid A synthesis and IL-1 dependent alkaline phosphatase activity, respectively). A second peptide motif (VIEFITL) was identified and the corresponding peptide synthesised along with a reordered version (LTILINV) of the best fit peptide. Both failed to bind measurably with IL-1beta or inhibit the response to IL-1 in the two bioassays. This best fit peptide behaved very similarly, in terms of IL-1 binding and inhibition behaviour, to the original trigger loop antisense peptide. Reference to the recently released X-ray crystal structure of IL-1beta and the IL1-R1 extracellular domain shows that the best fit peptide motif in IL-1 R1 is not apparantly interacting with the IL-1 trigger loop, although both are close in space. The intriguing possibility exists that the best fit peptide motif could represent an alternative site for IL-1beta receptor interaction which has not thus far been identified.

Netea MG, Kullberg BJ, Boerman OC, Verschueren I, Dinarello CA, Van der Meer JW
Soluble murine IL-1 receptor type I induces release of constitutive IL-1 alpha.
J Immunol. 1999; 162: 4876-81
Display abstract
IL-1 alpha and IL-1 beta are proinflammatory cytokines involved in the pathogenesis of many infectious and noninfectious inflammatory diseases. To reduce IL-1 toxicity, extracellular domains of the soluble (s) IL-1R are shed from cell membranes and prevent triggering of cell-bound receptors. We investigated to what extent murine sIL-1RI can neutralize the IL-1 produced by LPS-stimulated macrophages. When mouse peritoneal macrophages were incubated with LPS, addition of sIL-1RI significantly inhibited the bioactivity of IL-1. Stimulation of cells with sIL-1RI alone induced no bioactive IL-1. When immunoreactive cytokine concentrations were measured with specific radioimmunoassays, sIL-1RI alone appeared to induce a significant release of IL-1 alpha in a concentration-dependent manner. This effect was independent of new protein synthesis. The production of IL-1 beta or TNF-alpha was not influenced by sIL-1RI. There was no interference of sIL-1RI with the IL-1 alpha radioimmunoassay. In mice, an i.v. injection of sIL-RI alone induced a rapid release of IL-1 alpha, but not of TNF-alpha or IL-1 beta. Treatment of mice with sIL-1RI improved the survival during a lethal infection with Candida albicans. In conclusion, sIL-1RI induces a rapid release of IL-1 alpha from cells, as well as into the systemic circulation. Although this IL-1 alpha may be inactivated in circulation by the same sIL-1RI, this phenomenon probably has immunostimulatory effects at local levels where the sIL-1RI-induced IL-1 alpha acts in a paracrine or autocrine manner.

Siemion IZ, Kluczyk A, Wieczorek Z
Anti-IL-1 activity of peptide fragments of IL-1 family proteins.
Peptides. 1998; 19: 373-82
Display abstract
A series of peptides containing retro-tuftsin- and tuftsin-like motifs from IL-1 proteins inhibits IL-1-induced IL-2 production and reduces the humoral immune response, thus supporting our hypothesis that tuftsin (Thr-Lys-Pro-Arg)-IL-1 competition depends on the presence of such motifs in IL-1 proteins. Some other peptides from regions of IL-1 responsible for receptor binding were also active, with peptide Ile-Thr-Gly-Ser-Glu (III) from IL-1alpha (residues 98-102), not only strongly affecting IL-2 production, but also suppressing the immune response; the analogue of hexapeptide Val-Thr-Lys-Phe-Tyr-Phe from the C-terminal part of IL-lra, with Lys replaced by Asp, was as efficient as Val-Thr-Lys-Phe-Tyr-Phe with respect to IL-1 competition.

Adashi EY
The potential role of interleukin-1 in the ovulatory process: an evolving hypothesis.
Mol Cell Endocrinol. 1998; 140: 77-81
Display abstract
Despite the apparent preliminary nature of the observations cited herein, there is every reason to believe that continued investigation will provide new and meaningful insight relevant to the understanding of the complex interactions between the various cellular components of the ovary. If recent progress is any indication, the next decade may reveal that intraovarian cytokine messengers, as well as a host of growth factors, have major roles throughout the ovarian life cycle.

Born TL, Thomassen E, Bird TA, Sims JE
Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling.
J Biol Chem. 1998; 273: 29445-50
Display abstract
We have identified a novel member of the interleukin-1 (IL-1) receptor family, which we have termed AcPL. In transient transfection assays, we were unable to demonstrate a role for AcPL in IL-1-induced activation of NFkappaB. Interleukin-18 (interferon-gamma-inducing factor) is another member of the IL-1 family of cytokines, and it has recently been shown that IL-18 has a weak affinity for IL-1R-rp1. We examined whether AcPL might function alone or in concert with IL-1R-rp1 to mediate IL-18 signaling. We found that both IL-1R-rp1 and AcPL expression were required for induction of NFkappaB activity and for activation of c-Jun N-terminal kinase in response to IL-18. Furthermore, a dominant negative version of AcPL specifically inhibited IL-18 signaling. In vitro immunoprecipitation assays demonstrated that AcPL alone was unable to bind IL-18 with any appreciable affinity. We propose that although IL-1R-rp1 binds the cytokine, IL-1R-rp1 and AcPL proteins are both required for IL-18 signaling, analogous to the requirement for both IL-1R and IL-1RAcP in IL-1-mediated responses.

Roux-Lombard P
The interleukin-1 family.
Eur Cytokine Netw. 1998; 9: 565-76

Bresnihan B, Cunnane G
Interleukin-1 receptor antagonist.
Rheum Dis Clin North Am. 1998; 24: 615-28
Display abstract
There are three members of the IL-1 gene family: IL-1 alpha, IL-1 beta, and IL-1ra, IL-1 alpha, and IL-1 beta are both antagonist molecules with many proinflammatory effects. IL-1ra is an antagonist molecule that can inhibit the effect of IL-1 alpha and IL-1 beta by specifically blocking the IL-1 receptor on target effector cells. IL-1 alpha and IL-1 beta are considered to be pivotal cytokines in the pathogenesis of many inflammatory diseases. Anti-IL-1 treatment has been shown to cause amelioration of arthritis in animal models and in RA, suggesting that IL-1ra may be an important therapeutic option in the future management of RA.

Yu PW et al.
Regulation of bovine interleukin-1 receptors.
Vet Immunol Immunopathol. 1998; 63: 21-5
Display abstract
Interleukin-1 is a key player in inflammation and the immune response. The interleukin-1 family consists of three ligands (IL-1 alpha, IL-1 beta, and the IL-1 receptor antagonist) and two receptors (IL-1RI and IL-1RII). Previous studies suggest a dynamic relationship among these receptors and ligands that regulates the magnitude and extent of IL-1 mediated activities. Our laboratory has cloned and sequenced the bovine type I and II interleukin-1 receptors, and has begun to investigate their regulation in bovine leukocytes in vitro and in vivo. IL-1RI and IL-1RII mRNA levels were upregulated in vitro by various mediators, including dexamethasone, rBoIL-4, rBoGM-CSF, and rHuTNF alpha. Conversely, IL-1RI mRNA levels were down-regulated by IFN-gamma. An in vivo study indicated that IL-1RII mRNA levels increased earlier than IL-1RI mRNA levels in dexamethasone-treated cattle. These findings suggest that early upregulation of IL-1RII, which is a decoy receptor, may be part of the anti-inflammatory action of glucocorticoids. Our investigations suggest that anti-inflammatory agents increase expression of the biologically inactive IL-1RII, as compared with the biologically active IL-1RI, in bovine leukocytes.

van der Laken CJ et al.
In vivo expression of interleukin-1 receptors during various experimentally induced inflammatory conditions.
J Infect Dis. 1998; 177: 1398-401
Display abstract
Systemically administered interleukin-1 (IL-1) has been shown to preferentially bind to IL-1 receptors (IL-1Rs) in inflammation. Using radiolabeled IL-1alpha and molecular methods to assess gene expression for these receptors, the in vivo behavior of these receptors was investigated in a number of experimental inflammatory conditions. The uptake of 125I-labeled IL-1alpha in inflammatory foci significantly correlated with the mRNA expression for the type I and type II IL-1Rs (P < .05). Type II IL-1R mRNA showed a greater increase in expression than type I IL-1R mRNA. In neutropenic mice, inflammatory lesions, which are devoid of granulocytes, significantly lower 125I-labeled IL-1alpha uptake (P < .001), and type II IL-1R mRNA expression (P < .005) was found. Thus, there is strong up-regulation of IL-1Rs at sites of focal inflammation. Of interest, this mainly involved the type II IL-1R on granulocytes, which is not involved in signal transduction.

Cremona S, Laye S, Dantzer R, Parnet P
Blockade of brain type II interleukin-1 receptors potentiates IL1beta-induced anorexia in mice.
Neurosci Lett. 1998; 246: 101-4
Display abstract
Interleukin-1beta (IL1beta) peripheral activities are mediated by type I IL1 receptors (IL1RI), whereas type II IL1 receptors (IL1RII) act as 'decoy' targets. To study the functionality of IL1RII in the brain, mice were treated with an intracerebroventricular injection of a neutralising MoAb directed against IL1RII (4E2, 1 microg) followed by recombinant rat IL1beta at a dose (2 ng) that produced a moderate but significant decrease of food intake 1 h 30 min after injection. The administration of 4E2 to IL-1beta treated mice significantly potentiated IL1beta-induced decrease in food intake without altering hypothermia. The effects of IL1beta were abrogated in the positive control group treated with IL1ra (2 microg, i.c.v). These results suggest that brain IL1RII down-regulate the effects of IL1beta on its cell targets in the brain.

Kovalovsky D et al.
The Th1 and Th2 cytokines IFN-gamma and IL-4 antagonize the inhibition of monocyte IL-1 receptor antagonist by glucocorticoids: involvement of IL-1.
Eur J Immunol. 1998; 28: 2075-85
Display abstract
Monocytes express IL-1 and IL-1 receptor antagonist (IL-1Ra) in response to lipopolysaccharide (LPS). IL-1 self-induction contributes to the increase in IL-1 following LPS stimulation. LPS-stimulated IL-1 and IL-1Ra production are inhibited by glucocorticoids. In the present work we examined the regulation of IL-1Ra by Th1 cytokine IFN-gamma, Th2 cytokine IL-4, glucocorticoids and IL-1 in human monocytes. We demonstrate that IL-1 contributes to LPS-induced IL-1 Ra expression as shown by IL-1 blockade in LPS-stimulated monocytes using a specific anti-IL-1beta antibody or recombinant IL-1Ra. Glucocorticoids inhibited IL-1beta-stimulated IL-1Ra mRNA expression and protein production. Glucocorticoids inhibited both IL-1-mediated and non-mediated LPS stimulation of IL-1Ra expression. Both IFN-gamma and IL-4 reversed the inhibitory effect of glucocorticoids on IL-1Ra expression and secretion. The effect of IFN-gamma was blocked by pretreatment of monocytes with an anti-IL-1beta blocking antibody, whereas the effect of IL-4 could not be blocked, demonstrating that IFN-gamma acts through a mechanism dependent on endogenous IL-1 production, whereas IL-4 acts through an IL-1-independent one. Consistent with this finding, IFN-gamma (but not IL-4) failed to reverse the inhibitory effect of glucocorticoids when stimulated by IL-1, and only IL-4 combined with IL-1 showed synergism resulting in an increase in IL-1 Ra production. The differential regulation and involvement of IL-1 in the expression of IL-1Ra by IFN-gamma, IL-4 and glucocorticoids sets the level of monocyte responsiveness during the Th1 or Th2 responses.

Schneider H, Pitossi F, Balschun D, Wagner A, del Rey A, Besedovsky HO
A neuromodulatory role of interleukin-1beta in the hippocampus.
Proc Natl Acad Sci U S A. 1998; 95: 7778-83
Display abstract
It is widely accepted that interleukin-1beta (IL-1beta), a cytokine produced not only by immune cells but also by glial cells and certain neurons influences brain functions during infectious and inflammatory processes. It is still unclear, however, whether IL-1 production is triggered under nonpathological conditions during activation of a discrete neuronal population and whether this production has functional implications. Here, we show in vivo and in vitro that IL-1beta gene expression is substantially increased during long-term potentiation of synaptic transmission, a process considered to underlie certain forms of learning and memory. The increase in gene expression was long lasting, specific to potentiation, and could be prevented by blockade of potentiation with the N-methyl-D-aspartate (NMDA) receptor antagonist, (+/-)-2-amino-5-phosphonopentanoic acid (AP-5). Furthermore, blockade of IL-1 receptors by the specific interleukin-1 receptor antagonist (IL-1ra) resulted in a reversible impairment of long-term potentiation maintenance without affecting its induction. These results show for the first time that the production of biologically significant amounts of IL-1beta in the brain can be induced by a sustained increase in the activity of a discrete population of neurons and suggest a physiological involvement of this cytokine in synaptic plasticity.

Malinowsky D, Lundkvist J, Laye S, Bartfai T
Interleukin-1 receptor accessory protein interacts with the type II interleukin-1 receptor.
FEBS Lett. 1998; 429: 299-302
Display abstract
Stably transfected HEK-293 cells express on their surface the murine type II IL-1 receptor (mIL-1RII) as demonstrated by FACS analysis using the mAb 4E2, however binding of [125I]-hrIL-1beta to these cells is nearly absent. Saturable high affinity binding of [125I]-hrIL-1beta is observed when the murine IL-1 receptor accessory protein (mIL-1RAcP) is coexpressed with mIL-1RII. Binding of [125I]-hrIL-1beta to mIL-1RII-mIL-1RAcP complex can be inhibited either with antibodies to mIL-1RII (mAb 4E2), or by antibodies to mIL-1RAcP (mAb 4C5). The number of high affinity binding sites in cells stably transfected with the cDNA for mIL-1RII is dependent on the dose of cDNA for mIL-1RAcP used to transfect the cells. The high affinity complex between mIL-1RII and mIL-1RAcP is not preformed by interaction between the intracellular domains of these two transmembrane proteins, rather it appears to require the extracellular portions of mIL-1RII and mIL-1RAcP and the presence of a ligand. We suggest that in addition to its earlier described decoy receptor role, IL-1RII may modulate the responsiveness of cells to IL-1 by binding the IL-1RAcP in unproductive/non-signalling complexes and thus reducing the number of signalling IL-1RI-IL-1RAcP-agonist complexes when IL-1 is bound.

Shimauchi H, Takayama S, Imai-Tanaka T, Okada H
Balance of interleukin-1 beta and interleukin-1 receptor antagonist in human periapical lesions.
J Endod. 1998; 24: 116-9
Display abstract
Interleukin-1 beta (IL-1 beta) has been considered as a major potent mediator of bone resorption and implicated in the development of human periapical lesions. Among naturally occurring interleukin-1 (IL-1) inhibitors, IL-1 receptor antagonist (IL-1ra) is a 22 kDa protein that shares homology with IL-1 beta and IL-1 alpha, binds to IL-1 receptor with similar affinity to IL-1, and has no known agonist properties. In this study, we measured the periapical exudate (PE) levels of IL-1 beta and IL-1ra from human periapical lesions. PE samples were collected from root canals during routine endodontic treatments, and the enzyme-linked immunosorbent assay was used to measure PE-IL-1 beta and IL-1ra. Detectable levels of both IL-1 beta and IL-1ra were found in 25 of 29 clinical samples. Relatively high levels of IL-1ra compared with IL-1 beta (mean IL-1ra:IL-1 beta ratio = 128:7; range: 0.9 to 495.4), and significantly positive correlation between IL-1ra and IL-1 beta levels was found. The PE-IL-1ra:IL-1 beta ratios obtained from symptomatic lesions were significantly lower than those from asymptomatic lesions. These results suggest that IL-1ra-mediated IL-1 antagonism occurred to block locally produced IL-1 activity, and the balance of IL-1 to IL-1ra production may be crucial in the development of periapical lesions.

Ohguchi M et al.
Activin A regulates the production of mature interleukin-1beta and interleukin-1 receptor antagonist in human monocytic cells.
J Interferon Cytokine Res. 1998; 18: 491-8
Display abstract
Activin A, a member of the transforming growth factor-beta (TGF-beta) family, is produced by a variety of cells and implicated in the regulation of the reproductive endocrine system, mesoderm induction, and erythropoiesis. In the present study, we showed that activin A inhibited the production of interleukin-1beta (IL-1beta), a potent proinflammatory cytokine, and enhanced the production of IL-1 receptor antagonist (IL-1ra), in activated THP-1 and U-937 human monocytic cells, resulting in the reduction of IL-1 biologic activity. Northern blot analysis revealed that activin A had no effect on mRNA accumulation of IL-1beta and IL-1ra, indicating that activin A regulates IL-1beta and IL-1ra production at a posttranscriptional level. As it is well known that an inactive precursor form of IL-1beta (pro-IL-1beta) is converted to an active mature form (mature IL-1beta), we examined the expression levels of pro-IL-1beta and mature IL-1beta by immunoblot analysis. Although activin A inhibited the production of mature IL-1beta in activated U-937 cells, the relative protein expression of pro-IL-1beta was unaltered by activin A, suggesting that activin A inhibits IL-1beta production by blocking proteolytic conversion of pro-IL-1beta into mature IL-1beta. Taken together, these findings suggest that activin A may function as an anti-inflammatory cytokine by modulating mature IL-1beta and IL-1ra production in inflammatory sites.

Dinarello CA
Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist.
Int Rev Immunol. 1998; 16: 457-99
Display abstract
IL-1 (IL-1 alpha or IL-1 beta) is the prototypic "multifunctional" cytokine. Unlike the lymphocyte and colony stimulating growth factors, IL-1 affects nearly every cell type, and often in concert with other cytokines or small mediator molecules. Although some lymphocyte and colony stimulating growth factors may be therapeutically useful, IL-1 is a highly inflammatory cytokine and the margin between clinical benefit and unacceptable toxicity in humans is exceedingly narrow. In contrast, agents that reduce the production and/or activity of IL-1 are likely to have an impact on clinical medicine. In support of this concept, there is growing evidence that the production and activity of IL-1, particularly IL-1 beta, are tightly regulated events as if nature has placed specific "road blocks" to reduce the response to IL-1 during disease. In addition to controlling gene expression, synthesis and secretion, this regulation extends to surface receptors, soluble receptors and a receptor antagonist. Investigators have studied how production of the different members of the IL-1 family is controlled, the various biological activities of IL-1, the distinct and various functions of the IL-1 receptor (IL-1R) family and the complexity of intracellular signaling. Mice deficient in IL-1 beta, IL-1 beta converting enzyme (ICE) and IL-1R type I have also been studied. Humans have been injected with IL-1 (either IL-1 alpha or IL-1 beta) for enhancing bone marrow recovery and for cancer treatment. The IL-1 specific receptor antagonist (IL-1Ra) has also been tested in clinical trials.

Wesche H, Resch K, Martin MU
Effects of IL-1 receptor accessory protein on IL-1 binding.
FEBS Lett. 1998; 429: 303-6
Display abstract
Interleukin-1 (IL-1) is an important pro-inflammatory cytokine that exerts its diverse biological functions by binding to a receptor complex consisting of two transmembrane proteins, type I IL-1 receptor (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP). Both receptor chains are indispensable for IL-1 signaling, but only IL-1RI is able to bind the cytokine. The effects of IL-1RAcP on IL-1 binding are unclear. This study shows that although expression of IL-1RAcP does not alter the equilibrium dissociation constant of IL-1, it has an effect on the non-equilibrium binding modus, most likely due to changes in on/off rates. This defines an additional function of IL-1RAcP: it stabilizes the active IL-1 receptor complex.

Barak V, Nisman B, Polliack A, Vannier E, Dinarello CA
Correlation of serum levels of interleukin-1 family members with disease activity and response to treatment in hairy cell leukemia.
Eur Cytokine Netw. 1998; 9: 33-9
Display abstract
Hairy cell leukemia (HCL) is a well-recognized chronic lymphoproliferative disorder of B cell lineage, which may be regulated by growth factors including cytokines and cytokine antagonists. Previous studies have shown a good correlation between circulating soluble interleukin-2 receptor (sIL-2R) levels and disease activity and response to therapy was always associated with a decrease in sIL-2R levels. The interleukin-1 (IL-1) family of agonists and antagonists may also be involved in the regulation of hematopoietic malignancies. In the present study, we evaluated members of the IL-1 family (IL-1beta, IL-1 receptor antagonist (IL-1Ra) and IL-1 soluble receptors Type I and Type II (IL-1sRI and IL-1sRII) in 23 patients with HCL. Patients were classified according to the clinical state of their disease. Most were treated with 2-chloro-2'-deoxyadercosine (2-CDA) and treatment was associated with a significant decrease in the serum levels of sIL-2R, IL-1beta and IL-1sRII in patients achieving a complete or partial response. In contrast to the above, levels of IL-1Ra increased during response to treatment and clinical response to 2-CDA was associated with an increase of 122% in IL-1Ra levels, in parallel with a decrease of 63% in IL-1beta and 47% in IL-1sRII levels. These results suggest that the balance between IL-1beta, IL-2 and their soluble receptors or antagonists may be involved in the pathogenesis and immunoregulation of HCL. Serum levels of these cytokines may therefore be used to monitor therapeutic efficacy of therapy in HCL and to detect any residual disease.

Yoon DY, Dinarello CA
Antibodies to domains II and III of the IL-1 receptor accessory protein inhibit IL-1 beta activity but not binding: regulation of IL-1 responses is via type I receptor, not the accessory protein.
J Immunol. 1998; 160: 3170-9
Display abstract
The IL-1R accessory protein (IL-1RAcP) plays a role in IL-1R signaling by forming a complex with IL-1RI bound to the IL-1 ligand. We identified four hydrophilic peptide regions of the extracellular IL-1RAcP that may be available for complex formation (peptide 1, 71-83 domain I; peptide 2, 204-211 domain II; peptide 3, 282-292 domain III; and peptide 4, 304-314 domain III). These peptides were synthesized, coupled to keyhole limpet hemocyanin, and used to produce rabbit antisera. Each affinity-purified antiserum showed specificity for the respective peptide without cross-reactivity. Anti-peptide 2, 3, and 4 recognized surface expression of IL-1RAcP on the Th2 D10S cells by FACS and inhibited IL-1-driven proliferation. Anti-peptide 4 recognized intact IL-1RAcP and soluble IL-1RAcP. Anti-IL-1RAcP-peptide 4, which targets the terminal segment of domain III, inhibited 80% of IL-1 beta-driven proliferation of D10S cells. However, these IL-1RAcP Abs had no effect on the activity of human or mouse IL-1 alpha. Whereas IL-1 beta down-regulated IL-1RI surface expression (p < 0.05), there was no change in the surface expression of IL-1RAcP. Moreover, murine IL-10 increased surface expression of IL-1RI, but did not affect expression of IL-1RAcP or the proliferation of D10S cells. Steady state levels of mRNA for IL-1RAcP and IL-1RI in D10S cells showed a similar pattern to that of surface expression of the respective receptors. We conclude that 1) blocking IL-1RAcP inhibits IL-1 signaling in D10S cells, 2) domains-II and III may be involved in complex formation with IL-1RI, 3) IL-1RAcP is not regulated as is IL-1RI in the same cells, and 4) IL-1 responsiveness is dependent on the expression of IL-1RI, not IL-1RAcP.

del Rey A, Monge-Arditi G, Besedovsky HO
Central and peripheral mechanisms contribute to the hypoglycemia induced by interleukin-1.
Ann N Y Acad Sci. 1998; 840: 153-61
Display abstract
The impact that neuroendocrine effects of cytokines have on general host homeostasis is reflected by the profound metabolic changes observed in parallel. The effect of interleukin-1 beta (IL-1 beta) on glucose blood levels serves as an example. Although IL-1 beta stimulates glucocorticoid output and decreases hepatic glycogen content, hypoglycemia is concomitantly detected in adult and newborn mice. This effect is observed even during fasting and is probably due to increased glucose transport into tissues. Even after a glucose load, IL-1-treated animals remain hypoglycemic, suggesting that central mechanisms that control the set point of glucose homeostasis are affected. Low doses of IL-1 beta injected i.c.v. can also induce hypoglycemia. Furthermore, central blockade of IL-1 receptors partially inhibits the hypoglycemia induced by peripheral administration of IL-1 beta. On the other hand, central depletion of catecholamines exacerbates IL-1-induced hypoglycemia. IL-1-mediated effects on glucose levels might be directed at providing more energy supply to tissues during processes with high metabolic demands.

Alheim K, Bartfai T
The interleukin-1 system: receptors, ligands, and ICE in the brain and their involvement in the fever response.
Ann N Y Acad Sci. 1998; 840: 51-8
Display abstract
The ligands and the receptors of the interleukin 1 (IL-1) system constitute a highly inducible set of proteins whose expression in infection and inflammation is of key importance in the host defense. The IL-1 system participates in the stimulation of the immune system, the neuroendocrine system, and the neuroimmune system. The major soluble and secreted agonist of the system, IL-1 beta, has been studied by mutational and transgenic approaches. Furthermore, involvement of the signal-transducing type I IL-1 receptor (IL-1RI), in fever and other responses, has been studied by null mutation technique. We describe the inducible expression of the two agonists, IL-1 alpha (31 kDa and 17 kDa) and IL-1 beta (17 kDa) and of the IL-1 receptor subtypes IL-1RI and IL-1RII in the brain and in the adrenals (as well as in the pituitary cell line AtT20). We also describe an additional member of the IL-1 family: the IL-1 receptor antagonist (IL-1ra), an endogenous antagonist to IL-1 alpha and IL-1 beta. Furthermore, the IL-1 beta-converting enzyme (ICE) and its differential regulation and expression in brain and adrenals is also discussed. Fever is a systemic response to intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) injection of IL-1 alpha or IL-1 beta. IL-1 beta-induced fever can be blocked by IL-1ra pretreatment. The fever response seems to be mediated via the IL-1RI as inferred from studies with receptor subtype-specific mutants of IL-1 beta and from studies in IL-1RI knock-out (IL-1RI KO) mice. IL-1 beta knock-out mice showed a hyperresponsive fever to both IL-1 agonists, IL-1 alpha and IL-1 beta, as well as to LPS.

Mantovani A, Muzio M, Ghezzi P, Colotta C, Introna M
Regulation of inhibitory pathways of the interleukin-1 system.
Ann N Y Acad Sci. 1998; 840: 338-51
Display abstract
The IL-1 system includes two agonists, converting enzymes, antagonists, and two receptors (R). New elements and functions in the system will be discussed, including (a) cloning of a new isoform of the receptor antagonist; (b) further analysis of the type II IL-1-binding molecule as a decoy R. The modulation of IL-1R by chemotactic signals was recently investigated. It was found that chemoattractants cause rapid release of the type II decoy R from myelomonocytic cells with a t1/2 of 30 sec. Induction of decoy R release represents an early event in the multistep process of recruitment. It may serve to block the systemic action of IL-1 leaking from sites of inflammation, while preserving responsiveness in situ. We recently cloned the first long pentraxin, PTX3 (human and mouse, cDNA and genomic) as an IL-1-inducible gene. The structural and functional features of this molecule as well as initial evidence of involvement in human pathology will be discussed.

Mehraban F, Kasturi S
Gene transfer of type 1 interleukin-1 receptor extracellular-domain complementary DNA into rabbit synovial cell line HIG-82 results in cellular blockade of interleukin-1 signal transduction.
Arthritis Rheum. 1998; 41: 515-24
Display abstract
OBJECTIVE: To produce, by means of expression cloning, a soluble type 1 interleukin-1 receptor (sIL-1R), and to assess its inhibitory properties on the IL-1 pathway. METHODS: High-affinity IL-1R sites were identified in a human chondrosarcoma cell line by means of 125I-IL-1beta binding. A 1-kilobase complementary DNA (cDNA) encoding the ligand-binding domain of the type 1 IL-1R was cloned by using polymerase chain reaction, and the cDNA was inserted into a mammalian expression vector pRc/CMV. The sIL-1R expression vector was transfected into a rabbit synovial cell line (HIG-82) and a stably transfected cell population was selected. The production of sIL-1R was confirmed in the medium of transfected cells using 125I-IL-1beta binding. 35S labeling of transfected cultures, followed by immunoprecipitation and gel electrophoresis, was used to characterize the size of the recombinant sIL-1R. Stromelysin and IL-1alpha steady-state messenger RNA (mRNA) levels were assessed by Northern blotting. Prostaglandin E2 (PGE2) release was measured by enzyme-linked immunosorbent assay. RESULTS: IL-1R on the surface of HIG-82 cells bound 125I-IL-1beta with an equilibrium dissociation constant (Kd) of 67.3 +/- 7.8 pM (mean +/- SD). Transfection of the sIL-1R expression vector into a synovial cell line in vitro resulted in the appearance of an sIL-1R protein that bound 125I-IL-1beta with high affinity in the medium (Kd = 108 +/- 5 pM). Two protein bands (Mr 42 kd and 47 kd) were immunoprecipitated with an antibody against type 1 T cell-derived sIL-1R. Expression of sIL-1R was accompanied by a marked decrease in both stromelysin and IL-1alpha steady-state mRNA levels. In conjunction, there was a significant inhibition of basal and IL-1-stimulated PGE2 released by sIL-1R-producing cells. CONCLUSION: The data suggest that gene transfer of type 1 sIL-1R into the synovium may be an effective means of inhibiting IL-1-induced metalloproteinase expression and inflammatory responses.

Akarsu ES, House RV, Coceani F
Formation of interleukin-6 in the brain of the febrile cat: relationship to interleukin-1.
Brain Res. 1998; 803: 137-43
Display abstract
Previous investigations have shown that interleukin-6 (IL-6), unlike other cytokines, is produced in larger amounts in the brain of the febrile animal regardless of the route, peripheral vs. central, of pyrogen administration. In addition, depending on the experimental condition IL-6 production may or may not require the prior induction of interleukin-1 (IL-1). The present study was carried out in the conscious cat to assess the importance of brain-derived IL-6 in the pathogenesis of fever and the interaction at that site between this cytokine and IL-1. IL-6 was detected in cerebrospinal fluid (CSF) collected at rest and its levels increased during the fever to intravenous (i.v.) endotoxin. The IL-6 elevation, but not the fever, was reversed by pretreatment with intracerebroventricular (i.c.v.) IL-1 receptor antagonist (hIL-1ra). Conversely, when pyrogens (endotoxin, IL-1) were given i.c.v., i.c.v. hIL-1ra reduced the fever without altering significantly the associated rise in CSF IL-6. We conclude that IL-6 is formed in brain in response to both i.v. and i.c.v. pyrogens; however, its formation, whether requiring the prior induction of IL-1 or not, does not appear to be critical for the development of the fever. Blood-borne IL-6, unlike brain-derived IL-6, may still play a role in fever as a trigger of signal-transducing mechanisms operating across the blood-brain barrier.

Lin MT, Liu HH, Yang YL
Involvement of interleukin-1 receptor mechanisms in development of arterial hypotension in rat heatstroke.
Am J Physiol. 1997; 273: 20727-20727
Display abstract
Rats, under urethan anesthesia, were exposed to a high ambient temperature (42 degrees C) to induce heatstroke and to assess the hemodynamic changes associated with heatstroke. Compared with normothermic controls, rats with heatstroke showed higher values of colonic temperature, heart rate, and plasma levels of interleukin (IL)-1 but lower values of R wave amplitude, P-R and Q-T intervals, systolic wave amplitude, diastolic and dicrotic wave duration, mean arterial pressure, stroke volume, and cardiac output. Animals injected intravenously with an IL-1-receptor antagonist at the time of heatstroke induction were protected from some of the cardiovascular effects of heatstroke, such as depressed ventricular depolarization, decreased stroke volume, decreased cardiac output, and arterial hypotension. The hemodynamic changes associated with heatstroke could be mimicked by IL-1beta administration. Other cardiovascular parameters such as total peripheral vascular resistance were unaffected by heatstroke induction or IL-1beta treatment. The results indicate that a selective decline in stroke volume or ventricular depolarization resulting from increased plasma levels of IL-1 may be an important mechanism signaling arterial hypotension or circulatory failure in rat heatstroke.

Lundqvist EN, Egelrud T
Biologically active, alternatively processed interleukin-1 beta in psoriatic scales.
Eur J Immunol. 1997; 27: 2165-71
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The aims of the present work were to elucidate the biochemical properties of interleukin-1 beta (IL-1 beta) in psoriatic scales to get information on the processing of epidermal IL-1 beta in psoriasis, and to elucidate whether the IL-1 beta in psoriatic scales possesses biological activity. By means of ion exchange chromatography, IL-1 beta in extracts of psoriatic scales was purified to a stage where it could be analyzed with electrophoretic methods and immunoblotting. Compared to mature recombinant human IL-1 beta (Ala 117 IL-1 beta), IL-1 beta in psoriatic scales had a slightly higher apparent molecular mass and a more acidic isoelectric point, as revealed by two-dimensional electrophoresis under denaturing conditions. Isoelectric focusing under non-denaturing conditions of IL-1 beta partially purified from psoriatic scales, or from non-inflamed plantar stratum corneum (Nylander Lundqvist, E., Back, O. and Egelrud, T., J. Immunol. 1996. 157: 1699), and of mature IL-1 beta, followed by immunoblotting with IL-1 beta-specific antibodies, showed that psoriatic scales contained two components with IL-1 beta-like immunoreactivity which were isoelectric at pH 6.1 and 6.3, respectively. These components could also be detected in extracts of plantar stratum corneum, which also contained small amounts of an IL-1 beta-like component isoelectric at pH 6.9. Mature IL-1 beta was isoelectric at pH 6.9. No IL-1 beta-like biological activity could be detected in crude extracts of psoriatic scales. These extracts also contained high amounts of IL-1 receptor antagonist. Partially purified preparations of IL-1 beta from psoriatic scales, in which an apparently total separation of IL-1 beta and IL-1 receptor antagonist had been achieved, could induce expression of E-selectin in human umbilical vein endothelial cells. This activity was inhibited by antibodies specific for IL-1 beta, but not by antibodies specific for IL-1 alpha. It is concluded that psoriatic scales contain biologically active IL-1 beta, which has been processed by a mechanism which may be similar to that present in non-inflamed plantar stratum corneum, and which does not involve IL-1 beta converting enzyme.

Slotman GJ, Quinn JV, Wry PC, Brathwaite CE, Friedman BM
Unopposed interleukin-1 is necessary for increased plasma cytokine and eicosanoid levels to develop in severe sepsis.
Ann Surg. 1997; 226: 77-84
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OBJECTIVE: The purpose of the study was to identify the changes in plasma prostaglandin, leukotriene, and cytokine levels during clinical severe sepsis for which interleukin-1 was necessary. SUMMARY BACKGROUND DATA: Circulating prostaglandins, leukotrienes, and cytokines have been implicated as causative agents of systemic inflammation due to sepsis. However, interactions between interleukin-1 and the other cytokine and eicosanoid mediators of severe sepsis are not well-defined. METHODS: As part of two sequential multisite, prospective, randomized, double-blind, placebo-controlled clinical trials, 37 patients with severe sepsis received interleukin-1 receptor antagonist (IL-1ra) 100-mg bolus followed by 2 mg/kg per hour intravenously for 72 hours (n = 20) or placebo (n = 17). Plasma thromboxane B2 (TxB2), prostaglandin 6-keto-F1alpha (PGI), leukotriene B4 (LTB4), leukotriene C4D4E4 (LTC4D4E4), interleukin-1 beta (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay before study drug infusion (baseline) and at 24, 48, and 72 hours after the beginning of the study drug infusion. RESULTS: Differences between placebo and IL-1ra for plasma LTB4 were not significant, but only IL-1ra LTB4 increased from baseline. Plasma TxB2, PGI, LTC4D4E4, TNF, and IL-6, expressed as % baseline, decreased significantly in patients receiving IL-1ra compared with the placebo group (p < 0.05), whereas plasma IL-1 increased significantly. CONCLUSIONS: Interleukin-1 may be a necessary mediator of increased circulating PGI, TxB2, LTC4D4E4, TNF, and IL-6 levels in patients with severe sepsis. Plasma IL-1 and LTB4 are increased with infusion of IL-1 receptor antagonist. The clinical significance of IL-1 in modifying circulating eicosanoid and cytokine concentrations in clinical sepsis is not clear from the data.

Korherr C, Hofmeister R, Wesche H, Falk W
A critical role for interleukin-1 receptor accessory protein in interleukin-1 signaling.
Eur J Immunol. 1997; 27: 262-7
Display abstract
Interleukin-1 (IL-1) is a central molecule in inflammation and immune responses whose pleiotropic activities are mediated by the type I IL-1 receptor (IL-1RI). The IL-1RI alone on the cell surface is silent after binding of the ligand. We show that the recently identified IL-1RI accessory protein (IL-1RAcP) converts the silent into a fully functional IL-1RI complex. Although transfection of IL-1RAcP into IL-1RAcP-deficient EL4D6/76 cells did not alter the binding kinetics or dissociation constants of the 125I-labeled IL-1alpha/IL-1RI complex, a very early event, internalization of the activated receptor complex, and a late event, IL-1-stimulated IL-2 production, were successfully restored. Therefore, recruitment of IL-1RAcP is a critical early step in the signaling cascade mediated by the IL-1RI activation complex.

Stefanelli S, Corti E, Montanini N, Denaro M, Sarubbi E
Inhibitors of type-I interleukin-1 receptor from microbial metabolites.
J Antibiot (Tokyo). 1997; 50: 484-9
Display abstract
We describe here the results of a screening program conducted to discover inhibitors of the type-I interleukin-1 receptor (IL-1RI) from samples of microbial origin. An innovative approach, based on automated, nonradioactive receptor binding assays has been employed. Specially prepared cell-free systems have allowed the use of high concentrations of microbial metabolites in the reaction mixtures with a low percentage of false positives. More than 30,000 microbial samples from different species of soil isolates have been tested and two interesting activities have been purified and characterized. One of these, isolated from Streptomyces sp. GE48009, was identified as niphimycin, an antifungal agent also known as scopafungin. Preliminary evidence suggests that this molecule and azalomycin F, a structural analogue, inhibit IL-IRI by virtue of their long-chain guanidinium moiety. The other activity, isolated from Aspergillus sp. GE49752, was identified as flavipin, a substituted o-phthalaldehyde.

McMahon GA, Garfinkel S, Prudovsky I, Hu X, Maciag T
Intracellular precursor interleukin (IL)-1alpha, but not mature IL-1alpha, is able to regulate human endothelial cell migration in vitro.
J Biol Chem. 1997; 272: 28202-5
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The human umbilical vein endothelial cell (HUVEC) has a finite lifespan in vitro, and senescent HUVEC contain elevated levels of the negative growth regulator interleukin (IL)-1alpha. IL-1alpha is translated as a signal peptide sequence-less cytosolic 31-kDa precursor (IL-1alpha p), which undergoes proteolytic activation to release the mature carboxyl terminus 17-kDa protein (IL-1alpha m). Both the IL-1alpha p and IL-1alpha m proteins are biologically active as exogenous cytokines. Interestingly, only IL-1alpha p contains a nuclear localization sequence between residues 79 and 85. To further study the role of intracellular IL-1alpha in the regulation of human endothelial cell function, a spontaneous HUVEC transformant was stably transfected with IL-1alpha p, IL-1alpha m, and the IL-1alpha p K82N mutant, which attenuates the nuclear traffic of IL-1alpha p. Interestingly, the IL-1alpha p transfectants were found to have a lower migratory potential than either IL-1alpha m or IL-1alpha p K82N transfectants, and the addition of the IL-1 receptor antagonist did not alter the migration of these cells. Immunofluorescence microscopy demonstrated that only the IL-1alpha p transfectants exhibited prominent staining for beta-catenin-associated cell-to-cell contacts, as well as pronounced vimentin intermediate filaments and actin cytoskeleton staining. These data suggest that IL-1alpha p, and not IL-1alpha m, may function as an intracellular regulator of the migratory capacity of the human endothelial cell and that the nuclear localization sequence present within IL-1alpha p may be involved in regulating this function.

Martin MU, Falk W
The interleukin-1 receptor complex and interleukin-1 signal transduction.
Eur Cytokine Netw. 1997; 8: 5-17
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The aim of this mini-review is to give an update on the current developments concerning the IL-1 plasma membrane receptor complex and the modes of signal transduction through the plasma membrane. The mechanisms of signal generation at the cytosolic side of the plasma membrane will be summarized. Possible coupling mechanisms to down-stream signalling elements will be discussed, which result in the complex activation of transcription factors responsible for the cellular responses to IL-1. It is not the aim of this review to extensively summarize IL-1 induced cytosolic kinase cascades and activation of transcription factors.

Ammala M, Nyman T, Salmi A, Rutanen EM
The interleukin-1 system in gestational tissues at term: effect of labour.
Placenta. 1997; 18: 717-23
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Previous studies suggest that the interleukin-1 (IL-1) system is involved in preterm labour, at least in cases associated with intrauterine infection. To investigate the effect of term labour without infection on the IL-1 system, the messenger ribonucleic acid (mRNA) expression of IL-1 beta, IL-1 receptor type I (IL-1R tI), IL-1 receptor antagonist (IL-1ra), and IL-1 beta converting enzyme (ICE) were examined by Northern blot analysis and by reverse transcriptase-polymerase chain reaction (RT-PCR) in paired samples of decidua and placenta obtained from women having spontaneous vaginal delivery (group 1) or elective caesarean section (group 2) at term. In addition, concentrations of IL-1 beta and IL-1ra proteins were measured by ELISA in paired decidual and placental cytosols. In all decidual samples, IL-1 beta mRNA was expressed strongly, and the IL-1 beta concentration was 40- to 50-fold higher than in paired placental samples, in which the signal for IL-1 beta mRNA could be detected by RT-PCR only, and the amount of IL-1 beta protein was undetectable or very low. A comparison between the study groups revealed that the decidual IL-1 beta mRNA level tended to be higher in group 1, and the median IL-1 beta concentration in decidual cytosols was significantly higher in group 1 than in group 2 (P < 0.05). The IL-1R tI mRNA transcript was stronger in decidual than in paired placental samples in both groups. The mRNAs encoding ICE and IL-1ra were detected by RT-PCR in decidual and placental samples from both groups. The IL-1ra concentration tended to be higher in decidual cytosols than in paired placental cytosols, but there was no difference between the study groups. The IL-1ra/IL-1 beta ratio was significantly lower in decidual samples in women with spontaneous labour than in women without labour (P < 0.05). The results of this study confirm that decidua is the major site of IL-1 beta production and action in term gestational tissues. Furthermore, the results show that the major change in decidual/placental IL-1 system during parturition is the increase in decidual IL-1 beta production. Whether the increased IL-1 beta production precedes or is a consequence of labour, remains still unclear.

Vigers GP, Anderson LJ, Caffes P, Brandhuber BJ
Crystal structure of the type-I interleukin-1 receptor complexed with interleukin-1beta.
Nature. 1997; 386: 190-4
Display abstract
Interleukin-1 (IL-1) is an important mediator of inflammatory disease. The IL-1 family currently consists of two agonists, IL-1alpha and IL-1beta, and one antagonist, IL-1ra. Each of these molecules binds to the type I IL-1 receptor (IL1R). The binding of IL-1alpha or IL-1beta to IL1R is an early step in IL-1 signal transduction and blocking this interaction may therefore be a useful target for the development of new drugs. Here we report the three-dimensional structure of IL-1beta bound to the extracellular domain of IL1R (s-IL1R) at 2.5 A resolution. IL-1beta binds to s-IL1R with a 1:1 stoichiometry. The crystal structure shows that s-IL1R consists of three immunoglobulin-like domains which wrap around IL-1beta in a manner distinct from the structures of previously described cytokine-receptor complexes. The two receptor-binding regions on IL-1beta identified by site-directed mutagenesis both contact the receptor: one binds to the first two domains of the receptor, while the other binds exclusively to the third domain.

Dinarello CA
Induction of interleukin-1 and interleukin-1 receptor antagonist.
Semin Oncol. 1997; 24: 981993-981993
Display abstract
Drugs that affect the production or action, or both, of the pleiotropic inflammatory cytokine interleukin-1 (IL-1) are predicted to have a significant impact on a variety of human diseases. The biochemical properties of IL-1 and the IL-1 receptor antagonist, the mechanism for their production, and the factors that regulate their release are discussed here. The association of IL-1 with various disease states is also reviewed. Various classes of drugs that can be used to manipulate the production of IL-1 and IL- I receptor antagonist are described. Interferon-alpha2b is a potent inhibitor in vitro of the induction of IL-1 and tumor necrosis factor by IL-1 and can induce high circulating levels of the anti-inflammatory soluble tumor necrosis factor receptor and IL-1 receptor antagonist in humans. Thus, interferon-alpha2b exhibits potent anti-inflammatory effects.

Ge Y, Ezzell RM, Clark BD, Loiselle PM, Amato SF, Warren HS
Relationship of tissue and cellular interleukin-1 and lipopolysaccharide after endotoxemia and bacteremia.
J Infect Dis. 1997; 176: 1313-21
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Distributions of immunoreactive interleukin-1 (IL-1) and lipopolysaccharide (LPS) were studied in the tissues of rats after intravenous injection of purified LPS or live Escherichia coli bacteria. IL-1 staining in the spleen peaked at 4-8 h, colocalized with LPS in marginal zone macrophages, and was undetectable 24 h after injection, whereas LPS staining peaked at 24 h and was detectable for 4 weeks. The tissue IL-1 response was similar for LPS and live bacteria. Thus, tissue IL-1 is down-regulated within hours despite maintenance of LPS in the same cells for weeks. Macrophages in liver and lung had only slight IL-1 staining despite intense staining for LPS. Tissue IL-1 production appears to be differentially regulated after gram-negative bacteremia; LPS cleared by liver and lung macrophages elicit minimal IL-1, whereas there is high local IL-1 production in the marginal zone of the spleen that may increase immune responses to bacterial wall antigens.

Lee RT, Briggs WH, Cheng GC, Rossiter HB, Libby P, Kupper T
Mechanical deformation promotes secretion of IL-1 alpha and IL-1 receptor antagonist.
J Immunol. 1997; 159: 5084-8
Display abstract
Both IL-1 alpha and IL-1 beta lack an N terminus secretory sequence, and the mechanism of secretion of these pleiotropic cytokines is incompletely understood. The epidermis contains large quantities of IL-1 alpha in keratinocytes, which may play a role in inducing endothelial adhesion molecules and promoting extravasation of leukocytes. Here we report that mechanical deformation of human keratinocytes leads to rapid release of IL-1 alpha, possibly through transient disruptions in the plasma membrane. Using a device that precisely controls the amplitude of strain on the culture substrate, we found by pulse-chase analysis, Western analysis, and ELISA that the release of IL-1 alpha is dependent on the amplitude of the strain. A cyclic strain of 14% released a small but significant quantity of IL-1 alpha, while strains of 33% released 66 +/- 9% of cytoplasmic IL-1 alpha over 1 h (p < 0.001). Release of IL-1 alpha was accompanied by rapid release of large stores of IL-1R antagonist, approximately 25 to 30 times greater by mass than the quantity of IL-1 alpha released, but only a small fraction of cytoplasmic lactate dehydrogenase. Media conditioned by mechanically stimulated keratinocytes induced expression of E-selectin by human vascular endothelial cells; induction of E-selectin was completely inhibited by an Ab to IL-1 alpha. Therefore, mechanical strain promotes the secretion of IL-1 alpha, and deformation of keratinocytes in the epidermis may activate vascular endothelium through mechanically released IL-1 alpha. This pathophysiologic mechanism may play a role in the anatomic localization of some inflammatory skin diseases, such as psoriasis, which occurs more commonly in locations where the dermis is subjected to repetitive stretch or trauma.

Brandolini L et al.
Interleukin-1 beta primes interleukin-8-stimulated chemotaxis and elastase release in human neutrophils via its type I receptor.
Eur Cytokine Netw. 1997; 8: 173-8
Display abstract
Interleukin-1 (IL-1) is a pleiotropic proinflammatory cytokine which binds to human neutrophils (PMN) and can directly or indirectly activate their functions. In this study we show that a brief exposure to IL-1 beta induces a potentiation of both PMN elastase release and chemotactic response to interleukin-8 (IL-8), the prototype of C-X-C chemokines. Priming by IL-1 beta was maximal at 100 ng/ml, was completely blocked in the presence of IL-1 receptor antagonist (IL-1ra) and, in the chemotaxis assay, was best observed at suboptimal (3-6 ng/ml) or inactive (0.75 ng/ml) concentrations of IL-8. Priming of PMN by IL-1 beta was completely blocked by M1, a specific antibody against the type I IL-1 receptor (IL-1RI). On the other hand M22, an antibody directed against the IL-1 decoy type II IL-1 receptor did not affect IL-1 beta action and slightly increased the priming effect. Thus, exclusively via its type I receptor, IL-1 beta can act on PMN at multiple levels, by promoting their accumulation in tissues through the induction of chemotactic factors (e.g. IL-8) and the upregulation of adhesion molecules, and by priming their response to chemotactic agonists.

Wieczorek Z, Kluczyk A, Slon-Usakiewicz JJ, Siemion IZ
A hexapeptide VTKFYF from C-terminal part of interleukin-1 receptor antagonist, an inhibitor of IL-1-IL-1 receptor interaction.
Pol J Pharmacol. 1997; 49: 107-17
Display abstract
In order to find the low-molecular-weight interleukin-1 (IL-1) inhibitors we synthesized a series of peptides, derived from three regions of interleukin-1 receptor antagonist (IL-1ra): N-terminal (residues 5-9), central (90-98) and C-terminal (143-148). The decision was based on the thorough analysis of structural and functional properties of IL-1 proteins and the resemblance of some fragments of IL-1ra to well-known immunomodulators, like thymopentin and tuftsin. The competition between our peptides and IL-1 was measured as the inhibition of IL-1 induced IL-2 production in LBRM/CTLL cell line system. The activity of tuftsin (TKPR), a peptide immunomodulator derived from IgG molecule, was also examined. All peptides presented some activity, although the most interesting results (when the range of activity and dose-dependence were taken into account) were obtained for tuftsin and peptide VTKFYF from the C-terminal part of IL-1ra, which is in agreement with the latest reports on the structure of IL-1ra-receptor complex.

van der Laken CJ et al.
Preferential localization of systemically administered radiolabeled interleukin 1alpha in experimental inflammation in mice by binding to the type II receptor.
J Clin Invest. 1997; 100: 2970-6
Display abstract
Previously, we have shown that systemically administered radiolabeled interleukin 1alpha (IL-1alpha) accumulates preferentially in inflammatory foci in mice. Since inflammation is characterized by influx of leukocytes, which represent IL-1 receptor (IL-1R) positive cells, radiolabeled IL-1 may specifically localize in inflammation by binding to its receptors on infiltrated leukocytes. This hypothesis was tested in a series of studies in mice with acute focal inflammations. Evidence for specific IL-1-IL-1R interaction in induced inflammation was found: microscopic autoradiography revealed that 125I-IL-1alpha localized at the site of inflammatory cells with time; 125I-myoglobin, a similar-sized protein with no known interactions in vivo, was not retained in the inflammation. Furthermore, the uptake 125I-IL-1alpha in inflammatory tissue was significantly lower in neutropenic mice than in immunocompetent mice (0.05+/-0.004 vs. 0.65+/-0.06% ID/g at 48 h after injection, P < 0.0007). Moreover, the uptake of 125I-IL-1alpha at the inflammatory site could be blocked with the anti-IL-1R type II antibody 4E2. At 48 h after injection, the uptake with and without blocking the type II IL-1R was 0.13+/-0.01 and 0. 65+/-0.05% ID/g, respectively (P < 0.0001). These in vivo studies provide evidence that systemically administered radiolabeled IL-1alpha localizes in inflammatory tissue by specific receptor binding, predominantly by binding to the type II IL-1R.

Prystowsky JB, Rege RV
Interleukin-1 mediates guinea pig gallbladder inflammation in vivo.
J Surg Res. 1997; 71: 123-6
Display abstract
Interleukin-1 (IL-1) is a cytokine with multiple immunologic and inflammatory properties. We previously demonstrated that lipopolysaccharide (LPS) stimulates release of IL-1, and IL-1 stimulates inflammation in guinea pig gallbladder in vivo. We hypothesized that IL-1 mediates LPS-induced guinea pig gallbladder inflammation in vivo. LPS and IL-1 were instilled into guinea pig gallbladder lumen alone (with cystic duct ligation) and with IL-1 ra and indomethacin, respectively (n = 4). Water transport across gallbladder mucosa, myeloperoxidase and IL-1 release from gallbladder tissue, and prostaglandin E2 (PGE2) in lumenal fluid were measured. Values for test agents and inhibitory agents were compared to saline controls using Student's t test (P < 0.05). Intralumenal LPS and IL-1 both stimulated gallbladder inflammation. LPS-induced and IL-1-induced inflammation were inhibited by both IL-1 ra and indomethacin. LPS stimulated IL-1 release and IL-1 itself caused gallbladder inflammation. LPS stimulated gallbladder inflammation as manifest by increased myeloperoxidase and PGE2 release, and water secretion into the gallbladder lumen. The inflammatory effects of LPS were inhibited by IL-1 ra. Taken together, these findings indicate that IL-1 is a mediator of LPS-induced guinea pig gallbladder inflammation in vivo.

Fink G, Yang J, Carter G, Norman J
Acute pancreatitis-induced enzyme release and necrosis are attenuated by IL-1 antagonism through an indirect mechanism.
J Surg Res. 1997; 67: 94-7
Display abstract
Interleukin-1 beta (IL-1) is a proinflammatory cytokine which is produced within the pancreas during acute pancreatitis reaching levels which are toxic to many cell types. Since antagonism of this cytokine provides dramatic survival benefits during lethal pancreatitis, we hypothesized that IL-1 had direct secretagogue and cytolytic effects within the pancreas. The effect of IL-1 on pancreatic exocrine function and tissue viability was assessed in vivo by blockade of IL-1 with varying doses of IL-1 receptor antagonist (IL-1ra) prior to the induction of either moderate (caerulein-induced) or severe (choline deficient diet-induced) necrotizing pancreatitis. Subsequent in vitro studies were conducted to determine the direct effect of IL-1 on dispersed rat acini prepared through collagenase digestion. Amylase release was measured after a 30-min incubation with varying doses of recombinant IL-1 beta. Viability was determined in the presence of IL-1 via trypan blue exclusion at multiple time points. Blockade of the IL-1 receptor decreased pancreatic amylase release and tissue necrosis in both models of pancreatitis in a dose-dependent fashion (1.0 mg/kg, P = NS; 10 mg/kg, P < 0.05; 100 mg/kg, P < 0.05). Despite these in vivo findings, the addition of IL-1 to acini in vitro had no effect on exocrine function and failed to decrease acini viability (both, P = NS). Pancreatic amylase release and tissue necrosis are significantly attenuated during experimental pancreatitis by IL-1 antagonism. These changes do not appear to be due to the direct action of IL-1 on pancreatic acini and are likely due to more complex interactions between acini and cytokine-producing leukocytes.

Matsumoto Y, Kato M, Tamada Y, Mori H, Ohashi M
Enhancement of interleukin-1 alpha mediated autocrine growth of cultured human keratinocytes by sho-saiko-to.
Jpn J Pharmacol. 1997; 73: 333-6
Display abstract
We investigated the effects of Sho-saiko-to, the most commonly used herbal medicine in Japan, on the production of interleukin (IL)-1 alpha by cultured human epidermal keratinocytes. IL-1 alpha production was significantly promoted by treatment with 100 or 500 micrograms/ml Sho-saiko-to for 24 or 48 hr. Expression of IL-1 alpha receptors was the most markedly upregulated after treatment with 500 micrograms/ml Sho-saiko-to for 24 hr and with 100 or 500 micrograms/ml for 48 hr; these cells showed the characteristics of multilayered differentiated keratinocytes. The presence of an anti-IL-1 alpha antibody during the treatment with 500 micrograms/ml of Sho-saiko-to for 24 or 48 hr or with 100 micrograms/ml for 48 hr significantly down-regulated the synthesis by the keratinocytes and induced damages in them. Keratinocytes treated with Sho-saiko-to might produce IL-1 alpha and express IL-1 alpha receptors. IL-1 alpha may regulate the proliferation and differentiation of keratinocytes after Sho-saiko-to treatment. These findings suggest that Sho-saiko-to enhances the autocrine growth mediated by IL-1 alpha.

Penton Rol G, Polentarutti N, Sironi M, Saccani S, Introna M, Mantovani A
Gene transfer-mediated expression of physiological numbers of the type II decoy receptor in a myelomonocytic cellular context dampens the response to interleukin-1.
Eur Cytokine Netw. 1997; 8: 265-9
Display abstract
Available information suggests that the type II IL-1 receptor (RII) is a nonsignaling molecule which acts as a decoy for IL-1. The decoy function model for RII was supported by gene transfer experiments in fibroblasts and keratinocytes. Therefore, inhibition of IL-1 responsiveness after decoy RII gene transfer could reflect a non-physiological cellular context and receptor number. In the present study, constructs encoding RII or a cytoplasmic deletion mutant (delta 372-398) were transfected into U937 cells which express only low levels of RI detectable by RT-PCR. Gene transfer resulted in receptor numbers (approximately equal to 10(3)/cell) of the same order of magnitude as that found in normal myelomonocytic cells. Transfer of RII or a cytoplasmic deletion mutant into U937 did not increase responsiveness to IL-1, as assessed by IL-8 expression and production; it actually considerably dampened it. These results are consistent with the view that in a myelomonocytic cellular context, RII does not contribute to signaling and represents a unique pathway of negative regulation of the IL-1 system.

Hill AG, Siegel J, Rounds J, Wilmore DW
Metabolic responses to interleukin-1: centrally and peripherally mediated.
Ann Surg. 1997; 225: 246-51
Display abstract
OBJECTIVE: The purpose of this study was to differentiate between the catabolic effects of interleukin-1 (IL-1) when infused into the central nervous system or into the periphery. SUMMARY BACKGROUND DATA: After injury and infection, IL-1 has been found in the central nervous system. Chronic intracerebrovascular infusion of IL-1 produces protein catabolism, anorexia, and fever. However, IL-1 may act directly on liver and bone marrow to elicit metabolic responses. Although IL-1 is thought to be involved in a number of metabolic responses associated with injury-inflammation, the sites of action are unclear. METHODS: Rats were implanted with chronic infusion pumps and received diluent or three doses of IL-1 infused subcutaneously for 6 days, and a variety of response variables were measured. In a second study, doses were adjusted so that similar systemic catabolic responses were obtained from peripheral and intracerebroventricular infusion of IL-1. The acute-phase responses then were compared in the two groups of animals receiving IL-1 by different routes. RESULT: Subcutaneously infused IL-1 elicited catabolic responses in a dose-response manner. Similar catabolic responses were achieved by infusing one tenth of the dose of IL-1 given subcutaneously into the central nervous system. Although similar systemic responses (protein catabolism, anorexia, fever, and weight loss) were observed with both routes of infusion, the subcutaneous infusion produced a much greater lymphocytosis, elevation in acute-phase reactants, and fall in serum iron and albumin. CONCLUSIONS: The IL-1 appears to have different effects depending on the site of production and site of action. Regionalization of signal proteins such as IL-1 should be taken into consideration when devising specific anticytokine treatment strategies.

Oelmann E et al.
Autocrine interleukin-1 receptor antagonist can support malignant growth of glioblastoma by blocking growth-inhibiting autocrine loop of interleukin-1.
Int J Cancer. 1997; 71: 1066-76
Display abstract
In situ hybridization (ISH) of human glioblastoma tissue sections revealed expression of interleukin-1 (IL-1)alpha and/or beta and IL-1 receptor types I and II (IL-1R I and II) in the majority of cases evaluable. To understand the function of IL-1-family members in human glioblastomas, we have studied 6 glioblastoma cell lines. RT-PCR, ISH, ELISA and 125I-IL-1-binding assays revealed expression of IL-1 and high-affinity receptors for human (h)IL-1 in all but 1 cell line. Using a colony growth assay in semi-solid media for testing serial plating efficacy (PE, number of colonies per number of cells seeded in %), only the IL-1R-negative cell line was not influenced by recombinant human (rh)IL-1alpha or -beta, whereas IL-1 down-regulated the self-renewal of clonogenic cells of the other glioblastomas. Tritiated thymidine uptake was down-regulated by rhIL-1 in all cell lines studied. Cell viability remained unchanged by rhIL-1. Wherever growth modulation by rhIL-1 was detected, it could be reversed by either soluble IL-1R I or II or by rhIL-1 receptor antagonist (ra). IL-1ra not only was able to reverse rhIL-1-induced growth modulation but alone could modulate glioblastoma growth in comparison with control in cell lines producing IL-1. Our results show the presence of public autocrine loops for IL-1 leading to growth inhibition in some glioblastomas. To understand these loops, we have studied expression and function of IL-1ra in glioblastomas. ISH of human glioblastoma tissue sections revealed expression of hIL-1ra in all 8 cases evaluable. In 4 of 6 cell lines, IL-1ra was found in the supernatant under constitutive conditions, the IL-1R-negative line being among the 2 non-producers. The other non-producing cell line, HTB 17, showed expression of hIL-1R II. Most interestingly, a neutralizing antibody against IL-1ra down-regulated growth of IL-1- and IL-1ra-producing glioblastoma cells to approx. 30% of the controls. Thus, public autocrine loops for IL-1 in human glioblastomas exist and result in growth inhibition. An autocrine production of IL-1-antagonizing molecules such as IL-1ra by these tumors can counteract this IL-1 function and represent a basic escape mechanism supporting malignant growth in some glioblastomas.

Hofbauer LC, Muhlberg T, Konig A, Heufelder G, Schworm HD, Heufelder AE
Soluble interleukin-1 receptor antagonist serum levels in smokers and nonsmokers with Graves' ophthalmopathy undergoing orbital radiotherapy.
J Clin Endocrinol Metab. 1997; 82: 2244-7
Display abstract
Interleukin-1 (IL-1) plays an important role in the pathogenesis of Graves' ophthalmopathy (GO). Impaired antagonism of the proinflammatory cytokine IL-1 by the naturally occurring IL-1 receptor antagonist (IL-1RA) has been implicated in the initiation and perpetuation of various autoimmune diseases and may play a role in the evolution of GO. Cigarette smoking appears to adversely affect the course of GO. We have evaluated the course of IL-1 alpha, IL-1 beta, and soluble IL-1RA (sIL-1RA) serum levels in smokers and nonsmokers with GO undergoing orbital radiotherapy (OR). We prospectively studied the eye status of 27 randomly selected patients (mean age 47.3 +/- 11.0 yr; 20 females; 18 smokers) with active, moderately severe GO before and 3 and 6 months following OR, respectively. None had received any previous treatment for GO, and all patients were kept euthyroid on carbimazole. Serum concentrations of IL-1 alpha, IL-1 beta, and sIL-1RA were measured using highly sensitive enzyme linked immunosorbent assay systems. Baseline sIL-1RA levels were negatively correlated with the number of cigarettes smoked before and following OR (P < 0.0001). Patients with no or minor therapeutic response to OR (n = 8), all of whom were smokers, revealed mean baseline sIL-1RA levels of 114 +/- 85 pg/mL, which increased to 172 +/- 103 pg/mL at 3 months and 149 +/- 96 pg/mL at 6 months after initiation of OR, respectively. By contrast, patients with a good clinical response (n = 19, 9 nonsmokers), revealed significantly higher baseline sIL-1RA levels at 294 +/- 148 pg/mL (P = 0.004), which increased to 845 +/- 668 pg/mL at 3 months (P = 0.01) and 634 +/- 337 pg/mL at 6 months (P < 0.001), respectively, following initiation of OR. Serum concentrations of IL-1 alpha IL-1 beta were below 3.9 pg/mL in all patients with GO who were studied, and were not correlated with gender, age, smoking status, clinical course, or outcome. Low baseline levels and impaired surge of sIL-1RA serum levels following OR were strongly correlated with smoking status and a less favorable therapeutic outcome in patients with active, moderately severe GO. Measurement of sIL-1RA may contribute to predict the therapeutic response to OR in patients with active, moderately severe GO. Strategies designed to raise local or systemic concentrations of sIL-1RA may be of benefit to patients with GO.

Sonti G, Flynn MC, Plata-Salaman CR
Interleukin-1 (IL-1) receptor type I mediates anorexia but not adipsia induced by centrally administered IL-1beta.
Physiol Behav. 1997; 62: 1179-83
Display abstract
IL-1beta induces anorexia and adipsia. Here, we report that intracerebroventricular (ICV) pretreatment with an antisense (but not sense) phosphothio-oligodeoxynucleotide to the IL-1 receptor type I (IL-1RI, 1.28 microg or 239 pmol twice daily for 3.5 days before IL-1beta plus antisense) inhibits the anorexia, but not the adipsia induced by the ICV administration of 2.0 ng IL-1beta/rat (a dose that yields estimated pathophysiological concentrations in the cerebrospinal fluid). The mean 2 h food intake decrease in response to IL-1beta was 5.6% (n = 10) in the antisense- and 43% in the sense (n = 9)-treated groups; the mean 2 h water intake decrease was 40% in the antisense- and 39% in the sense-treated groups. The intraperitoneal administration of IL-1RI antisense, in doses equivalent to those administered centrally, had no effect on the anorexic effect induced by ICV administered IL-1beta; this indicates a direct action in the central nervous system. The results suggest that: i) IL-1RI is involved in the short-term anorexigenic, but not the adipsogenic effect induced by centrally administered IL-1beta; and ii) the approach presented using antisense strategies is applicable to study the molecular basis of IL-1 mediated behaviors.

Huang C, Chen HP, Cheng JS
[Interleukin-1 and ischemic brain damage]
Sheng Li Ke Xue Jin Zhan. 1997; 28: 175-7

Ohmoto Y, Ogushi F, Muraguchi M, Yamakawa M, Sone S
Age-related increase of autoantibodies to interleukin 1 alpha in healthy Japanese blood donors.
J Med Invest. 1997; 44: 89-94
Display abstract
Although autoantibodies to interleukin-1 alpha (IL-1 alpha autoantibodies) are known to be present in sera of apparently healthy humans, their frequency of occurrence and significance are unclear. To determine the prevalence of detectable IL-1 alpha autoantibodies in normal human blood, we screened the plasma of blood donors (6290 subjects: 3977 men and 2313 women, ages 16 to 64 yr) by a radioimmununoassay which we developed using a method that could detect over 5 ng/ml. Moreover, we investigated immunoglobulin class of IL-1 alpha autoantibodies and also their function. IL-1 alpha autoantibodies were detected in 14.6% of the 6290 donors. Their frequency was higher in males than females (16.6% vs. 11.2%, p < 0.01) and increased with age in both sexes. The proportion of subjects with a high IL-1 alpha autoantibodies titers also increased with age. We showed that IL-1 alpha autoantibodies were of the IgG class and that they had neutralizing function to IL-1 alpha by receptor assay. Neutralizing activity was only shown in plasma with concentration of IL-1 alpha autoantibodies, the level of which was over 1000 ng/ml. The affinity of the IL-1 alpha autoantibodies in plasma was between 2.1 x 10(-10) and 1.2 x 10(-9) M (mean 6.4 x 10(-10)M). Our results provide a basis for comparison with IL-1 alpha autoantibodies prevalence between healthy states and disease states, and suggest that IL-1 alpha autoantibodies may play a significant role in modulating the effects of excessive IL-1 alpha at local site or in systemic regions.

Bluthe RM, Dantzer R, Kelley KW
Central mediation of the effects of interleukin-1 on social exploration and body weight in mice.
Psychoneuroendocrinology. 1997; 22: 1-11
Display abstract
To study the role of central IL-1 receptors in the effects of recombinant human IL-1 beta (IL-1 beta) on behavior and body weight, intracerebroventricular (i.c.v.) injection of the specific antagonist of IL-1 receptors, IL-1ra, was administered to mice injected intraperitoneally (i.p.) and i.c.v. with various doses of IL-1 beta. Doses of 500 ng i.p. IL-1 beta and 900 pg i.c.v. IL-1 beta induced a comparable decrease in social behavior and loss of body weight. Pretreatment with IL-1ra (1.8 micrograms/mouse, i.c.v.) blocked the effects of i.c.v. IL-1 beta (900 pg/mouse) on social behavior. i.c.v. IL-1ra (3.6 micrograms/mouse) also attenuated the effects of i.p. IL-1 beta (500 ng/mouse) on social behavior and change in body weight, suggesting that the effects of peripheral IL-1 beta are centrally mediated.

Hirao T, Aoki H, Ichikawa H, Sato Y
Characterization of an interleukin 1 receptor antagonist protein released from ultraviolet-irradiated epidermal sheet.
J Dermatol Sci. 1997; 14: 189-98
Display abstract
An interleukin 1 (IL-1) inhibitor was detected in the culture supernatant of mouse epidermal sheet which had been irradiated with middle-wavelength ultraviolet (UVB) either in vitro or in vivo. Properties of the IL-1 inhibitor were consistent with those of IL-1 receptor antagonist (IL-1ra), i.e., approximate molecular size of 17 kDa by gel filtration, specific inhibition of IL-1-induced thymocyte proliferation, inhibition of binding of IL-1 to IL-1 receptor on the T-cell surface, and reactivity to anti-mouse IL-1ra antibody shown by immunoblotting and enzyme-linked immunosorbent assay (ELISA). These results indicate that this IL-1 inhibitor, which appears to be identical with IL-1ra, was released from the epidermis upon UVB irradiation, and that the inhibitor may participate in the regulation of inflammation mediated by IL-1, as well as in the pathogenesis of ultraviolet (UV)-induced immunosuppression.

Simon C, Mercader A, Gimeno MJ, Pellicer A
The interleukin-1 system and human implantation.
Am J Reprod Immunol. 1997; 37: 64-72
Display abstract
PROBLEM: Cytokines and growth factors are increasingly implicated in embryonic implantation. In the present study, we focus on the interleukin-1 system as an example of local regulator in human implantation. METHOD: Three different approaches are considered. First, we present evidence demonstrating its presence, regulation, and relevance on the human endometrium. Second, we demonstrate the presence of IL-1 system in the human embryo and the selective IL-1 release only when embryos were co-cultured with human endometrial epithelial cells (EEC) or EEC-conditioned media, indicating an obligate role of the endometrium in the regulation of the embryonic IL-1 system. Finally, we show data regarding the presence, hormonal regulation, and endometrial origin of IL-1 alpha, IL-beta, and IL-1ra levels in the endometrial fluid inside the endometrial cavity. Specifically, we present the IL-1 intracavitary microenvironment surrounding the human embryo at the apposition phase. RESULTS: This work suggests that the IL-1 system seems to be relevant for human endometrial and embryonic physiology. Furthermore, this family of molecules must be considered as a relevant paracrine language displayed by both partners that may be important to endometrial and embryonic crosstalk during embryonic implantation.

Murray CA, McGahon B, McBennett S, Lynch MA
Interleukin-1 beta inhibits glutamate release in hippocampus of young, but not aged, rats.
Neurobiol Aging. 1997; 18: 343-8
Display abstract
The proinflammatory cytokine, interleukin-1, is synthesized in neuronal and glial cells and is released in response to stress/injury. IL-1 exerts profound effects on the central nervous system, which include an inhibitory effect on synaptic activity in hippocampus, a brain area expressing a high density of IL-1 receptors. We report that IL-1 beta has an inhibitory effect on KCl-stimulated release of glutamate and KC1-stimulated [45Ca] influx in synaptosomes prepared from hippocampus of 4-month-old rats. These effects were inhibited by the endogenous receptor antagonist, IL-1ra, and by the phospholipase A2 (PLA2) inhibitor, quinacrine, suggesting that IL-1 receptor activation is coupled to PLA2. An inhibitory effect of IL-1 beta on protein kinase C activity was also observed. KC1-induced calcium-dependent release and calcium influx, and protein kinase C activity were significantly decreased in hippocampal synaptosomes prepared from 22-month-old compared to 4-month-old animals. In contrast to the inhibitory effect of IL-1 beta in synaptosomes prepared from young adult animals, no effect was observed on release, calcium influx, or protein kinase C activity in synaptosomes prepared from aged animals. We report that there is an age-related increase in expression of IL-1 beta in hippocampus and propose that this change may underlie the attenuated responses to IL-1 beta in hippocampus of aged animals.

Silver RM, Edwin SS, Umar F, Dudley DJ, Branch DW, Mitchell MD
Bacterial lipopolysaccharide-mediated murine fetal death: the role of interleukin-1.
Am J Obstet Gynecol. 1997; 176: 544-9
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OBJECTIVE: Our purpose was to determine whether interleukin-1 is an important mediator of lipopolysaccharide-induced fetal death and, if so, whether interleukin-1 causes fetal death by inducing prostanoid formation in gestational tissues. STUDY DESIGN: Pregnant C3H/HeN mice were administered lipopolysaccharide, interleukin-1alpha, interleukin-beta, or vehicle on days 11 to 13 of pregnancy. Mice were killed 72 hours later and the fetal status was determined. Some mice were pretreated with anti-interleukin-1-receptor antibodies or indomethacin. Decidual explants were established from treated mice, and supernatants were assayed for interleukin-1beta and prostaglandin E2. RESULTS: Decidua taken from lipopolysaccharide-treated mice produced significantly increased amounts of interleukin-1beta, and pretreatment with anti-interleukin-1-receptor antibodies reduced the proportion of fetal deaths after lipopolysaccharide administration from 100% to 33%. The administration of interleukin-1alpha caused fetal death in a dose-dependent fashion, and decidua taken from interleukin-1-treated mice produced significantly increased amounts of prostaglandin E2. However, pretreatment with doses of indomethacin that abrogated decidual prostaglandin E2 production did not reduce the proportion of fetal death after interleukin-1alpha administration. CONCLUSIONS: Interleukin-1 is an important mediator of lipopolysaccharide-induced fetal death and causes fetal death by prostaglandin-independent effects.

Sullivan GM, Canfield SM, Lederman S, Xiao E, Ferin M, Wardlaw SL
Intracerebroventricular injection of interleukin-1 suppresses peripheral lymphocyte function in the primate.
Neuroimmunomodulation. 1997; 4: 12-8
Display abstract
The cytokine interleukin-1 (IL-1) can act within the brain to induce peripheral endocrine and immune effects. In the rodent intracerebroventricular (i.c.v.) injection of IL-1 activates the hypothalamic-pituitary-adrenal axis and suppresses peripheral immune function by a CRH-dependent mechanism. It is unknown if IL-1 can similarly act within the brain to cause peripheral immunosuppression in the primate and to what extent this could be attributed to the IL-1-induced increase in ACTH and cortisol levels. In this study we have characterized the pituitary-adrenal and peripheral lymphocyte responses to IL-1 alpha (4.2 micrograms) infused over 30 min into the lateral ventricle of ovariectomized monkeys (n = 5) as compared with responses to an intravenous (i.v.) ACTH infusion (1 microgram/h for 7 h; n = 4). Four serial blood samples were obtained for ACTH and cortisol determination and for lymphocyte isolation during a 1-hour baseline and for 7 h after IL-1 or ACTH. Lymphocyte proliferation was measured by 3H-thymidine uptake in response to stimulation with phytohemagglutinin. In all 5 animals, IL-1 alpha caused rapid and profound suppression of lymphocyte mitogen responsiveness for 7 h. Baseline lymphocyte proliferation was 51,800 +/- 9,780 cpm and suppressed to a nadir of 4.5% with a mean of 23% baseline over 7 h (p < 0.001). Mean ACTH and cortisol levels increased from 33 +/- (SEM) 4.6 pg/ml and 43 +/- 4.0 micrograms/dl, respectively, during the control period to 90 +/- 14 pg/ml and 56 +/- 2.6 micrograms/dl, respectively, after IL-1 (p < 0.01). Before i.v. ACTH, baseline lymphocyte proliferation was 49,400 +/- 2,820 cpm, and suppressed to a mean of 64% of baseline during ACTH infusion (p < 0.05). Mean ACTH and cortisol levels increased from 48 +/- 5.0 pg/ml and 43 +/- 2.0 micrograms/dl, respectively, to 170 +/- 34 pg/ml and 66 +/- 2.3 micrograms/dl, respectively, during the ACTH infusion (p < 0.01). Lymphocyte suppression after i.c.v. IL-1 was much more profound than after i.v. ACTH (p < 0.01); the area under the IL-1 response curve was 37% of the area under the ACTH response curve. These studies demonstrate for the first time in the primate that centrally injected IL-1 has a profound suppressive effect on lymphocyte function. They also show for the first time in any species that there appears to be a significant immunosuppressive message produced by i.c.v. IL-1 that is not accounted for by the associated increases in ACTH and cortisol.

Debets R et al.
The IL-1 system in psoriatic skin: IL-1 antagonist sphere of influence in lesional psoriatic epidermis.
J Immunol. 1997; 158: 2955-63
Display abstract
The epidermal expression of IL-1 in psoriasis is clearly altered, but data are still incomplete and poorly understood. To thoroughly study the IL-1 system in psoriasis, we semiquantitatively analyzed the expression of all currently characterized IL-1 isoforms and their receptors in parallel in both lesional (PP) and nonlesional psoriatic (PN) epidermis. Immunostaining of skin sections showed that IL-1alpha, located in the basal keratinocytes of normal control (NN) and PN epidermis, was significantly decreased to negligible levels in PP epidermis. IL-1 receptor antagonist (IL-1ra) and IL-1R type II (IL-1RII) were both significantly overexpressed in mutually exclusive compartments of PP epidermis, the suprabasal and basal compartment, respectively. A significant inverse correlation was found between the expressions of IL-1alpha and these two IL-1 antagonists, which may be inherent to the accelerated terminal differentiation of the psoriatic keratinocyte. In situ hybridization of IL-1(R) mRNAs confirmed the staining results. Levels of IL-1ra mRNA, however, were not increased in PP epidermis, suggesting that the overexpression of IL-1ra protein may be explained at the level of translation. The more sensitive PCR demonstrated a clearly increased expression of IL-1beta mRNA in PP epidermal cells (EC), which may be related to the inflammatory response in psoriasis. IL-1RI mRNA was clearly present in both PP and NN EC. The mRNA levels of the secreted IL-1ra isoform, but not intracellular IL-1raI and II, and IL-1RII were elevated in PP EC and paralleled those of IL-1beta. In summary, this study provides a defined phenotype of the complete epidermal IL-1 system in psoriasis; it shows that the expressions of IL-1(R) isoforms are coordinately altered, resulting in a predominance of IL-1 antagonists, which may represent a negative feedback response to IL-1 agonists, leading to a decreased IL-1 responsiveness.

Adashi EY
The potential role of IL-1 in the ovulatory process: an evolving hypothesis.
J Reprod Immunol. 1997; 35: 1-9
Display abstract
The intra-ovarian interleukin-1 (IL-1) system may be an intermediary in the ovulatory process. More specifically, it is hypothesized that intra-ovarian IL-1 may constitute a mediator of gonadotrophins in the induction of ovulation. The current evidence for and against this possibility is reviewed.

Kanai T et al.
Increased interleukin-1 and interleukin-1 receptor antagonist levels in cervical mucus in the ovulatory phase in comparison with the follicular phase.
Gynecol Obstet Invest. 1997; 43: 166-70
Display abstract
Interleukin-1 (IL-1) receptor antagonist (IL-1ra) levels in the cervical mucus of women in the ovulatory phase are significantly higher than those in the follicular phase. IL-1 titers of women in the ovulatory phase are also significantly higher than those in the follicular phase. A positive correlation between IL-1ra and IL-1 levels in the cervical mucus was observed. Immunohistochemistry using an anti-IL-1ra monoclonal antibody revealed positive staining in the epithelial cells of the endocervix. These results suggest that IL-1ra from cervical epithelial cells protects the reproductive system from the toxicity of IL-1 produced in the endocervix.

Glaccum MB et al.
Phenotypic and functional characterization of mice that lack the type I receptor for IL-1.
J Immunol. 1997; 159: 3364-71
Display abstract
IL-1 alpha and IL-1 beta bind to receptors termed the type I and type II IL-1 receptors. The type I IL-1 receptor is responsible for specific signaling, while the type II IL-1 receptor functions as a nonsignaling decoy receptor. To determine the effect of a defect in IL-1-mediated signaling, mice have been produced with a genetically disrupted type I IL-1 receptor gene. Mice lacking type I IL-1 receptors are of normal vigor and exhibit no overt phenotype. B cells from type I IL-1R-/- mice activated in vitro with anti-IgM do not proliferate in response to IL-1, but do so in response to IL-4. Injection of murine IL-1 alpha does not induce detectable serum IL-6 levels in type I IL-1R-/- mice, but equivalent levels are produced in response to LPS. Type I IL-1R-/- mice have normal serum Ig levels and generate equivalent primary and secondary Ab responses as wild-type mice. In response to LPS, acute phase protein mRNA induction are equivalent in type I IL-1R-/- and wild-type mice. Type I IL-1R-/- mice do not differ from control mice in susceptibility to either a lethal challenge with D-galactosamine plus LPS or high dose LPS. Interestingly, ICE-/-/type I IL-1R-/- double mutant mice are resistant to high dose LPS. Type I IL-1R-/- mice backcrossed to the C57BL/6 background were as equally resistant as wild-type mice to Listeria monocytogenes.

Rogausch H, del Rey A, Kabiersch A, Reschke W, Ortel J, Besedovsky H
Endotoxin impedes vasoconstriction in the spleen: role of endogenous interleukin-1 and sympathetic innervation.
Am J Physiol. 1997; 272: 204854-204854
Display abstract
Processes relevant for an appropriate immune response such as immune cell traffic and recirculation require a tight control of blood supply to lymphoid organs. Interactions between endogenous cytokines and sympathetic nerve fibers in lymphoid organs can contribute to this control. The results reported in this paper show that 1) administration of low doses of lipopolysaccharide (LPS), an endotoxin derived from gram-negative bacteria, causes an increase in splenic blood flow (SBF); 2) this increase is mediated by the production of endogenous interleukin-1 (IL-1); 3) the effect of LPS on SBF requires an intact splenic sympathetic innervation; 4) the LPS-induced increase in SBF is exerted at the postganglionic level; 5) the endotoxin inhibits the vasoconstriction induced by the in vivo stimulation of the splenic nerve but does not affect the vasoconstriction induced by norepinephrine (NE); and 6) although IL-1 and LPS stimulate general sympathetic activity as reflected by increased peripheral vascular resistance, they do not increase NE concentration in splenic dialysates. Together these in vivo results indicate that endogenous IL-1 affects blood supply to the spleen by inhibiting the sympathetic vasoconstrictor tonus at a postganglionic, prejunctional level. This effect is expected to be relevant for immune cell recirculation, homing, and traffic as well as antigen trapping in the spleen, an organ specialized in the control of these processes during immune responses.

Bujia J, Kim C, Ostos P, Sudhoff H, Kastenbauer E, Hultner L
Interleukin 1 (IL-1) and IL-1-receptor antagonist (IL-1-RA) in middle ear cholesteatoma: an analysis of protein production and biological activity.
Eur Arch Otorhinolaryngol. 1996; 253: 252-5
Display abstract
Cytokine networks are now presumed to play an essential role in the pathogenesis of middle ear cholesteatoma. Of the factors identified in cholesteatoma, interleukin-I (IL-1)-alpha appears to be especially important because of its stimulation of keratinocyte proliferation as well induction of bone resorption. To further characterize the possible role of IL-1 in the pathogenesis of cholesteatoma, we quantified the levels of IL-1 and IL-1-receptor antagonist (IL-1-RA) present using the bicinchonic acid protein assay and enzyme-linked immunosorbent assay (ELISA) on tissue extracts from 20 cholesteatoma specimens. The presence of biologically active IL-1 was also analyzed, using the cell line LBRM-33 and an ELISA for the detection of interleukin-2 (IL-2). Human skin obtained from the external ear canal was used as control. The amounts of IL-1-alpha in cholesteatoma (34.9 +/- 19.5) were higher than in human skin (6.7 +/- 2.8). The observed differences were statistically significant by Student's t-test (P < 0.01). Skin samples showed elevated concentrations of IL-1-RA (248.3 +/- 30.2) in comparison to that in the cholesteatoma (80.8 +/- 13.5). This was also statistically significant (P < 0.01). Whereas IL-1 activity was not detected in skin samples, all cholesteatoma specimens studied showed a stimulation effect on the production of IL-2 when incubated with the cell line LBRM-33. The results point to an over-expression of IL-1 concurrent with a decreased secretion of IL-1-RA in middle ear cholesteatoma. Furthermore IL-1-RA production is deficient relative to total IL-1 production, resulting in the presence of active IL-1.

Re F et al.
Inhibition of interleukin-1 responsiveness by type II receptor gene transfer: a surface "receptor" with anti-interleukin-1 function.
J Exp Med. 1996; 183: 1841-50
Display abstract
The hypothesis that the type II receptor (RII) acts as a decoy for interleukin-1 (IL-1) was tested by gene transfer in cells expressing only the type I receptor (8387 fibroblasts). RII-transfected cells showed defective responsiveness to IL-1 in terms of NFkappaB activation, cytokine gene expression and production. Blocking monoclonal antibodies against RII restored the capacity of RII-transfected cells to respond to IL-1 beta. Hence defective IL-1 responsiveness of RII-transfected cells requires surface expression of the molecule. RII-transfected cells showed normal responsiveness to TNF, which shares functional properties and elements in the signal transduction pathway with IL-1. Cells transfected with a deletion mutant of RII missing 26 of 29 amino acids of the cytoplasmic portion of the molecule showed impaired responsiveness to IL-2. Cells transfected with full-length or the cytoplasmic deletion mutant of RII released copious amounts of RII in the supernatant. However, transfected cells showed defective responsiveness to brief exposure to IL-1, in the absence of measurable released RII. These results indicate that impairment of the responsiveness to IL-1 following RII gene transfer was dependent upon surface expression of the molecule, specific for IL-1 and unaffected by truncation of the cytoplasmic portion. Thus, the type II "receptor" is a decoy surface molecule, regulated by antiinflammatory signals, whose only known function is to capture and block IL-1.

Galton BC
Cistron has guts.
Nature. 1996; 384: 401-401

De los Santos MJ et al.
Role of endometrial factors in regulating secretion of components of the immunoreactive human embryonic interleukin-1 system during embryonic development.
Biol Reprod. 1996; 54: 563-74
Display abstract
In the study reported here, we localized at the protein level the major components of the interleukin (IL)-1 system in the human embryo, and we investigated the endometrial factors influencing their secretion during embryonic development. To localize these components, we performed immunohistochemical experiments in 44 oocytes and 78 embryos. The following primary antibodies were used: monoclonal mouse anti-human IL-1 receptor type I (IL-1R tl), monoclonal mouse anti-human IL-1 beta, and polyclonal rabbit anti-human IL-1 receptor antagonist (IL-1ra). For embryo culture, human embryos at different developmental stages were cultured in 100-microliters drops of Ham's F-10 medium + 4 mg/ml BSA (n = 33), in 100-microliters drops of Menezo B2 culture medium (n = 18), or in wells with 1 ml of Menezo B2 culture medium (n = 8). For embryo coculture, endometrial stromal cells (ESC) and endometrial epithelial cells (EEC) were isolated from human secretory endometrium and cultured until confluence in 75% Dulbecco's Modified Eagle's Medium and 25% MCDB-105 containing antibiotics and supplemented with 10% charcoal-Dextran-treated fetal bovine serum. Individual human embryos were cocultured with experimental EEC and ESC (n = 23 and n = 4, respectively) for 5 days in 600-microliters drops of Menezo B2 medium, and conditioned medium was removed every 24 h. Human embryos were also cultured with EEC-conditioned medium (n = 9). IL-1 alpha, IL-1 beta, and IL-1ra levels were determined by ELISA in the 24-h culture- or coculture-conditioned media. Immunostaining confirmed the presence of IL-1 beta, IL-1ra, and IL-1R tl in oocytes and embryos in all stages analyzed, with no statistical differences. IL-1 alpha, IL-1 beta, and IL-1ra were absent in conditioned media of cultured embryos and embryos cocultured with ESC. However, when human embryos were cocultured with EEC or with EEC-conditioned medium alone, two different populations of embryos were observed: IL-1 producers (57% and 56%) and IL-1 nonproducers (43% and 44%, respectively). Finally, the IL-1 profile of a single human embryo cocultured with maternal EEC which successfully implanted and developed is presented, this pattern being similar to that described in the IL-1 producer population. These results demonstrate the presence of the IL-1 system in the human embryo. However, the selective release of IL-1 only when embryos were cocultured with EEC or EEC-conditioned medium indicates an obligatory role of the endometrium in the regulation of the embryonic IL-1 system. Furthermore, the differential embryonic production of IL-1 may be related to the implantation capability of the embryos.

Sarubbi E
Particle concentration fluorescence as an alternative to radioactivity for cytokine receptor binding assays.
J Immunol Methods. 1996; 198: 113-8
Display abstract
To detect inhibitors of the type-I interleukin-1 receptor in a safe and cost-effective nonisotopic environment, the use of particle concentration fluorescence (PCF) as a detection method for a high volume receptor binding assay (RBA) has been explored. A cell-free PCF-RBA has been developed using a soluble form of the type-I IL-1 receptor (sIL-1R), a nonneutralizing anti-sIL-1R monoclonal antibody and two fluorescein-labelled tracers: IL-1 alpha and IL-1ra fused to the Escherichia coli maltose binding protein (MBP-IL-1ra). Both ligands showed saturable specific binding (KA values in the 10(9) M-1 range), although signal intensity was about 3-fold higher with MBP-IL-1ra. The data presented here suggest that the combined use of recombinant DNA and PCF technologies can replace the traditional cell-based, radioactive RBA when screening for inhibitors of cytokine receptors.

Jobanputra P
Chondrocyte metalloproteinase activation through integrin receptors and interleukin-1: comment on the article by Arner and Tortorella.
Arthritis Rheum. 1996; 39: 709-11

Takahashi S, Kapas L, Fang J, Seyer JM, Wang Y, Krueger JM
An interleukin-1 receptor fragment inhibits spontaneous sleep and muramyl dipeptide-induced sleep in rabbits.
Am J Physiol. 1996; 271: 1018-1018
Display abstract
Interleukin-1 (IL-1) is hypothesized to be involved in physiological sleep regulation and in sleep responses occurring during infectious disease. If this hypothesis is correct, then inhibition of endogenous IL-1 should reduce both normal sleep and N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP)-induced sleep. MDP is a somnogenic substance derived from bacterial cell walls. We report here the effects of a synthetic IL-1 receptor fragment corresponding to amino acid residues 86-95 of the human type I IL-1 receptor (IL-1RF) on spontaneous sleep and IL-1 beta- and MDP-induced sleep and fever in rabbits. Two doses of the IL-1RF (25 and 50 micrograms) were injected into normal rabbits intracerebroventricularly (icv). Both doses significantly decreased spontaneous non-rapid eye movement sleep (NREMS) across a 22-h recording period. Pretreatment of rabbits with 25 micrograms of IL-1RF blocked the somnogenic actions of 10 ng icv IL-1. Similarly, central pretreatment of animals with 25 micrograms IL-1RF significantly attenuated the NREMS-promoting and REMS-suppressive actions of 150 pmol MDP injected centrally. The increase in NREMS and decrease in REMS induced by systemic injection of 12.5 micrograms/kg MDP were also significantly suppressed by central administration of 50 micrograms IL-1RF. In contrast, the febrile response induced by either intracerebroventricularly or intravenously injected MDP were not significantly affected by IL-1RF. These results support the hypothesis that endogenous, brain-derived IL-1 contributes to the maintenance of normal sleep and may mediate sleep responses to systemic as well as central bacterial infections.

Wieczorek Z, Kluczyk A, Slon-Usakiewicz JJ, Siemion IZ
The search for inhibitors of interleukin-1 based on the sequence of interleukin-1 receptor antagonist.
Biomed Pept Proteins Nucleic Acids. 1996; 2: 123-9
Display abstract
In order to find the low-molecular-weight interleukin-1 (IL-1) inhibitors, we synthesised a series of peptides, derived from three regions of interleukin-1 receptor antagonist (IL-1ra): N-terminal (residues 5-9), central (90-98) and C-terminal (143-148). The decision was based on the thorough analysis of structural and functional properties of IL-1 proteins and the resemblance of some fragments of IL-1ra to well-known immunomodulators, like thymopentin and tuftsin. The competition between our peptides and IL-1 were measured as the inhibition of IL-1 induced IL-2 production in LBRM/CTLL cell line system. All peptides presented some activity, although the most interesting results (when the range of activity and dose-dependence were taken into account) were obtained for tuftsin and peptide VTKFYF from the C-terminal part of IL-1ra.

Garrone P et al.
Generation and characterization of a human monoclonal autoantibody that acts as a high affinity interleukin-1 alpha specific inhibitor.
Mol Immunol. 1996; 33: 649-58
Display abstract
Interleukin-1 (IL-1) defines two polypeptides, IL-1 alpha and IL-1 beta, that possess a wide spectrum of biological effects. Two natural antagonists of IL-1 action have been characterized: the IL-1 receptor antagonist (IL-1Ra) and a soluble form of the type II IL-1 receptor. Neutralizing autoantibodies to IL-1 alpha have also been detected in sera of healthy individuals and patients with autoimmune or inflammatory diseases. To characterize such antibodies molecularly, we attempted to generate B cell clones producing anti-IL-1 alpha human monoclonal antibody (HuMAb) by combining Epstein-Barr virus-immortalization and CD40-activation of B lymphocytes from individuals with circulating anti-IL-1 alpha. We describe herein the generation and properties of a natural IgG4/kappa anti-IL-1 alpha monoclonal autoantibody, HuMAb X3, that bound specifically to human IL-1 alpha, but not to IL-1 beta and IL-1Ra, with a high affinity (Kd = 1.2 x 10(-10)M). HuMAb X3 inhibited IL-1 alpha binding to IL-1 receptors and neutralized biological activities of both recombinant and natural forms of IL-1 alpha. A recombinant form of HuMAb X3 was found to display identical specific IL-1 alpha antagonism. The presence of somatic mutations within X3 variable regions suggests an antigen-driven affinity maturation. This study extends the demonstration of the presence of high affinity neutralizing anti-IL-1 alpha autoantibodies that can function as a third type of IL-1 antagonist.

Alcami A, Smith GL
A mechanism for the inhibition of fever by a virus.
Proc Natl Acad Sci U S A. 1996; 93: 11029-34
Display abstract
Poxviruses encode proteins that block the activity of cytokines. Here we show that the study of such virulence factors can contribute to our understanding of not only virus pathogenesis but also the physiological role of cytokines. Fever is a nonspecific response to infection that contributes to host defense. Several cytokines induce an elevation of body temperature when injected into animals, but in naturally occurring fever it has been difficult to show that any cytokine has a critical role. We describe the first example of the suppression of fever by a virus and the molecular mechanism leading to it. Several vaccinia virus strains including smallpox vaccines express soluble interleukin 1 (IL-1) receptors, which bind IL-1 beta but not IL-1 alpha. These viruses prevent the febrile response in infected mice, whereas strains that naturally or through genetic engineering lack the receptor induce fever. Repair of the defective IL-1 beta inhibitor in the smallpox vaccine Copenhagen, a more virulent virus than the widely used vaccine strains Wyeth and Lister, suppresses fever and attenuates the disease. The vaccinia-induced fever was inhibited with antibodies to IL-1 beta. These findings provide strong evidence that IL-1 beta, and not other cytokines, is the major endogenous pyrogen in a poxvirus infection.

Jarry A, Vallette G, Branka JE, Laboisse C
Direct secretory effect of interleukin-1 via type I receptors in human colonic mucous epithelial cells (HT29-C1.16E).
Gut. 1996; 38: 240-2
Display abstract
The stable differentiated human colonic epithelial cell line, HT29-C1.16E, was used to study the effects of interleukin-1 (IL-1) on mucin exocytosis. The main findings include: (a) IL-1 stimulated a rapid release of mucin from filter grown HT29-C1.16E cells, this effect being dose related; (b) this secretory effect was abolished in the presence of the blocking monoclonal antibody M4 specific for IL-1 receptors type I, showing that IL-1 receptors type I mediated IL-1 action; (c) experiments based on chamber cultures showed that these receptors were located on the basolateral membranes of HT29-C1.16E cells; (d) finally, mRNA for IL-1 receptors type I were detected by reverse transcriptase-polymerase chain reaction in these cells. To extend these findings to the in vivo situation, the rapid stimulatory effect of IL-1 on mucin exocytosis may contribute to the wash out of noxious agents during mucosal inflammation.

Nikolic-Paterson DJ, Lan HY, Atkins RC
Interleukin-1 receptor antagonism.
Semin Nephrol. 1996; 16: 583-90
Display abstract
Interleukin-1 (IL-1) is a pro-inflammatory cytokine that exerts a wide range of biological effects. The recently identified IL-1 receptor antagonist (IL-1ra) has provided a tool for blocking IL-1 activity in vivo, leading to a detailed understanding of the role of this cytokine in the inflammatory response. The importance of IL-1 production in glomerulonephritis has been shown by the ability of IL-1ra treatment to suppress the induction and progression of experimental crescentic glomerulonephritis. Although further studies are required, IL-1ra treatment is an attractive adjunct therapy for patients with progressive glomerulonephritis.

Watanabe N, Kobayashi Y
[Processing and release of interleukin-1]
Seikagaku. 1996; 68: 1638-41

Niijima A
The afferent discharges from sensors for interleukin 1 beta in the hepatoportal system in the anesthetized rat.
J Auton Nerv Syst. 1996; 61: 287-91
Display abstract
The effect of intraportal administrations of interleukin 1 beta (IL-1 beta) on the afferent activity of the hepatic branch of the vagus nerve was observed in urethane anesthetized rats. An intraportal injection of IL-1 beta in doses of 10 pg and 100 pg per animal (300-400 g body wt.) resulted in dose-dependent increase in the afferent activity, which lasted about 70-100 min. Further, intraportal injection of IL-1 beta (100 pg) induced reflex activation of efferent activity of the splenic (sympathetic) nerve and vagal thymic nerve. This reflex activation was not observed in hepatic vagotomized rat and after an administration of the same dose of IL-1 beta into the systemic vein in normal rat. The results suggest the existence of sensors for IL-1 beta which send information on IL-1 beta in the portal venous blood to the central nervous system through the hepatic branch of the vagus nerve and play some role in reflex regulation of immune function.

Hopp TP
Interleukin-1 research.
Science. 1996; 273: 1781-1781

Bergh A, Damber JE, Hjertkvist M
Human chorionic gonadotrophin-induced testicular inflammation may be related to increased sensitivity to interleukin-1.
Int J Androl. 1996; 19: 229-36
Display abstract
Treatment of adult male rats with human chorionic gonadotrophin (hCG) results in an inflammation-like response in the testicular microcirculation. Polymorphonuclear (PMN) leukocytes accumulate in venules and vascular permeability is increased. The mechanism behind this response was studied. Treatment with an interleukin-1 receptor antagonist partly prevented the hCG induced accumulation of PMN leukocytes 4 h after treatment. Human recombinant interleukin-1 alpha (IL-1 alpha) and beta (IL-1 beta), serotonin, and histamine were injected intratesticularly on one side and saline injected on the contralateral side in both intact and hCG-pretreated adult rats. A low dose of IL-alpha (a dose that did not increase vascular permeability in unstimulated testes) increased vascular permeability in the testes of animals treated with hCG 4, 6 or 8 h earlier, but it was without effect in testes from rats treated with hCG 0,1, 2, 16 or 32 h prior to IL-1 injection. The sensitivity to the pro-inflammatory effect of locally injected IL-1 beta was also increased by hCG treatment. There was no increase in vascular permeability after local injection of a large dose of histamine or serotonin in either saline- or in hCG-pretreated animals. Hypothetically, the hCG-induced inflammation-like increase in testicular vascular permeability could be related to increased sensitivity to constitutively produced mediators such as IL-1.

Bankers-Fulbright JL, Kalli KR, McKean DJ
Interleukin-1 signal transduction.
Life Sci. 1996; 59: 61-83
Display abstract
Interleukin-1 (IL-1) is primarily an inflammatory cytokine, although it is capable of mediating a wide variety of effects on many different cell types. Nearly every known signal transduction pathway has been reported to be activated in response to IL-1. However, the significance of many of these signaling events is unclear, due to the use of different and sometimes unique cell lines in studying IL-1-initiated signal transduction. Complicating matters further is the lack of association in many studies between identified IL-1-induced signals and subsequent biological responses. In this article, we review what is known about IL-1 receptor signaling and, whenever possible, correlate signaling events to biological responses.

Quan N, Zhang Z, Emery M, Bonsall R, Weiss JM
Detection of interleukin-1 bioactivity in various brain regions of normal healthy rats.
Neuroimmunomodulation. 1996; 3: 47-55
Display abstract
Although interleukin-1 (IL-1) has been implicated in an array of brain functions, past studies usually have failed to detect IL-1 bioactivity in the brain of normal healthy animals. However, in view of the potency of IL-1 in brain, small amounts of this cytokine may normally act in brain, and such quantities can escape detection by assay methods usually employed. Although bioassays are highly sensitive for detecting IL-1, these can be compromised by molecules in brain tissue other than IL-1, and attempts to purify IL-1 from brain tissue can result in significant loss of IL-1 from samples. In this study, we have refined our method of assessing brain IL-1 bioactivity by first semi-isolating IL-1 with a Sephadex minicolumn and then measuring IL-1 activity with a sensitive D10 cell assay. To confirm that our assay was specific for IL-1, a monoclonal antibody against IL-1 receptor was used to block any observed IL-1 activity. We report here that IL-1 bioactivity can be reliably detected in both the cell-free supernatant and cell lysate of brainstem, cortex, diencephalon, and hippocampus of normal rat brain. These results lend support to some recent studies that found IL-1 may play important roles in the functions of normal brain.

Simon C et al.
Hormonal regulation of serum and endometrial IL-1 alpha, IL-1 beta and IL-1ra: IL-1 endometrial microenvironment of the human embryo at the apposition phase under physiological and supraphysiological steroid level conditions.
J Reprod Immunol. 1996; 31: 165-84
Display abstract
We have investigated serum and intracavitary levels of IL-1 alpha, IL-1 beta and IL-1ra from agonadal women undergoing mock cycles (n = 20) of oocyte donation as a clinical model of controlled hormonal stimulation. Further, we compared the intracavitary IL-1 alpha, IL-1 beta and IL-1ra levels in the microenvironment of the human embryo at the apposition phase, day 5 after progesterone (P) administration using two different clinical models: oocyte donation (n = 20) which provides physiological steroid levels and a higher implantation rate per embryo, and in vitro fertilization (n = 6) with supraphysiological hormonal levels and a lower implantation rate.

Holst H, Magnusson U
Commercially available antibodies to human interleukin-1 do not crossreact with porcine interleukin-1.
Zentralbl Veterinarmed [B]. 1996; 43: 317-9
Display abstract
Interleukin-1 (IL-1) is a key mediator in inflammatory processes. There are several immunoassays for human, but not porcine, IL-1 commercially available. Four of these were tested on porcine specimens. IL-1 was not detected, by any of the immunoassays, in cell culture supernatants with confirmed IL-1 activity in a bioassay. The results indicate that the tested antibodies to human IL-1 do not crossreact with porcine IL-1.

Norman JG et al.
Active interleukin-1 receptor required for maximal progression of acute pancreatitis.
Ann Surg. 1996; 223: 163-9
Display abstract
OBJECTIVE: The authors' aim was to determine the requirement for an active interleukin (IL)-1 receptor during the development and progression of acute pancreatitis. SUMMARY OF BACKGROUND DATA: Interleukin-1 is a pro- inflammatory cytokine that has been shown to be produced during acute pancreatitis. Earlier animal studies of moderate and severe pancreatitis have shown that blockade of this powerful mediator is associated with attenuated pancreatic destruction and dramatic increases in survival. The exact role played by IL-1 and the requirement for activation of its receptor in the initiation and progression of pancreatitis is unknown. METHODS: Conventional and IL-1 receptor ?knockout? animals were used in parallel experiments of acute pancreatitis induced by intraperitoneal injection of cerulean (50 microg/kg every 1 hour X 4). The conventional mouse strain had the IL-1 receptor blocked prophylactically by means of a recombinant IL-1 receptor antagonist (10 mg/kg injected intraperitoneally every 2 hours). The second mouse strain was genetically engineered by means of gene targeting in murine embryonic stem cells to be devoid of type 1 IL-1 receptor (IL-1 receptor knockout). Animals were killed at 0, 0.5, 1, 2, 4, and 8 hours, with the severity of pancreatitis determined by serum amylase, lipase, and IL-6 levels and blind histologic grading. Strain-specific controls were used for comparison. RESULTS: The genetic absence of the IL-1 receptor or its pharmacologic blockade resulted in significantly attenuated pancreatic vacuolization, edema, necrosis, inflammation, and enzyme release. Serum IL-6, a marker of inflammation severity, was dramatically decreased in both groups. CONCLUSIONS: Activation of the IL-1 receptor is not required for the development of pancreatitis but apparently is necessary for the maximal propagation of pancreatic injury and its associated inflammation.

Adashi EY
Immune modulators in the context of the ovulatory process: a role for interleukin-1.
Am J Reprod Immunol. 1996; 35: 190-4
Display abstract
Recent studies have established the existence of a complete intraovarian interleukin-1 system replete with ligands, receptors, and a receptor antagonist. This article examines the hypothesis that intraovarian IL-1 may play an intermediary role in the ovulatory process. More specifically, it is hypothesized that intraovarian IL-1 beta may constitute a mediator of gonadotropins in the induction of ovulation, an effector capable of coordinating and amplifying key components of the ovulatory cascade. The insight derived from this investigation may result the elucidation of some of the molecular events underlying the ovulatory process, in the delineation of the reproductive side effects of systemic anti-IL-1 therapy, and in potentially improved strategies for the promotion of fertility or its control.

Matsukawa A, Fukumoto T, Yoshinaga M
[Production of IL-1 ra and its biological significance in experimental arthritis of rabbits]
Nippon Seikeigeka Gakkai Zasshi. 1996; 70: 751-8

Mantovani A, Locati M, Allavena P, Sozzani S
The chemokine superfamily: crosstalk with the IL-1 system.
Immunobiology. 1996; 195: 522-49

Tan GH, Dutton CM, Bahn RS
Interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptor inhibit IL-1-induced glycosaminoglycan production in cultured human orbital fibroblasts from patients with Graves' ophthalmopathy.
J Clin Endocrinol Metab. 1996; 81: 449-52
Display abstract
An accumulation of glycosaminoglycans (GAG) is a feature characteristic of orbital connective tissues from patients with Graves' ophthalmopathy (GO) that leads directly to the clinical expressions of the disease. Interleukin-1 (IL-1), produced by macrophages and fibroblasts within the diseased orbit, stimulates GAG synthesis by orbital fibroblasts. We designed the current study to determine whether particular agents might block this effect and thus be useful in the treatment of GO. Orbital fibroblast cultures were grown to confluence and incubated for 48 h with IL-1 (1-10 U/mL) alone or IL-1 (10 U/mL) in combination with IL-1 receptor antagonist (IL-1ra; 1-40 ng/mL) or soluble IL-1 receptor (sIL-1R; 0.25-10 micrograms/mL). Cells were labeled with [3H]glucosamine and processed for GAG quantitation. The addition of IL-1 alone stimulated GAG synthesis by 73-176% (mean, 104%; P < 0.05). Significant inhibition of IL-1-stimulated GAG synthesis was observed after treatment of normal fibroblasts with IL-1ra at a concentration of 5 ng/mL (12.5-fold molar excess; mean, 33%; P < 0.05); essentially complete inhibition was achieved at 40 ng/mL (100-fold molar excess; mean, 86%; P < 0.05). Significant inhibition of GAG synthesis by sIL-1R was observed at a concentration of 0.5 microgram/mL (720-fold molar excess; mean, 79%; P < 0.05), and inhibition was essentially complete at 1 microgram/mL (1440-fold molar excess; mean, 89%; P < 0.05). IL-1ra and sIL-1R are potent inhibitors of IL-1-induced GAG production by cultured human orbital fibroblasts. Our results suggest that these two compounds, shown in early trials to be safe when administered parenterally, may be useful in the prevention or treatment of GO.

Guasch JF, Bertina RM, Reitsma PH
Five novel intragenic dimorphisms in the human interleukin-1 genes combine to high informativity.
Cytokine. 1996; 8: 598-602
Display abstract
The cytokine interleukin-1 (IL-1) plays a key role in the pathogenesis of inflammatory and immune diseases. Several disease-genotype association studies have addressed the question whether genetic determinants of outcome or severity of disease exist. These studies were hampered by the lack of highly polymorphic markers in the interleukin-1 beta (IL-1B) and IL-1 receptor antagonist (IL-1RN) genes. Polymorphisms in these two genes were searched for in order to increase informativity. Here a novel BsoF I dimorphism and the characterization and PCR detection of a previously identified Taq I polymorphism in the IL-1B gene is reported. Furthermore, in the IL-1RN gene four novel diallelic markers were identified. Little linkage disequilibrium is observed between the two markers in IL-1B gene. Similarly, some of the markers in IL-1RN gene show little linkage disequilibrium. Using the markers described here it is possible to reach a better level of informativity in genotype-disease association studies.

Takei Y, Chiba T, Nabeshima S, Naruoka M, Wada K, Onozaki K
D-mannose dimer introduced human recombinant interleukin- 1 alpha, NEO IL-1 alpha, exhibits altered tissue distribution in mice.
J Interferon Cytokine Res. 1996; 16: 333-6
Display abstract
Previous studies have demonstrated that the carbohydrate-introduced recombinant human IL-l alpha exhibited impairment in both biologic activities in all the experiments in vitro and receptor binding capacity compared with intact IL-l alpha. However, the glycosylated IL-l alpha exhibited selective activities in vivo. In this study, we compared the tissue distribution of IL-l alpha and IL-l alpha coupled with D-Mana (l-6)Man [Man2 alpha) (l-6)IL-l alpha] in mice. Mice were injected by intravenous and intraperitoneal routes with 2.0 mu g radiolabeled IL-l alpha. At 1 and 2 h after IP injection, the level of Man2 alpha) (l-6)IL-l alpha decreased twofold compared with that of IL-l alpha in kidney. In contrast, at 1 hour after administration, Man2 alpha) (l-6)IL-l alpha exhibited higher levels than IL-l alpha in blood, heart, and liver. No significant difference was observed in brain at each time point. IV injection demonstrated that Man2 alpha)(l-6)IL-l alpha decreased to approximately one-half the level of rhIL-l alpha in kidney. In contrast, Man(2 alpha) (l-6)IL-l alpha increased twofold over that of IL-l alpha in liver at 1 h after dosing. These findings are consistent with the result of IP injection. There was no significant difference between IL-l alpha and glycosylated IL-l alpha at 4 h after IV administration. These differences in tissue distribution may contribute to the selective activities of glycosylated IL-l alpha in vivo. The results also suggest that by coupling with mannose dimer, it is possible to develop neocytokines prone to liver distribution.

Rindfleisch MS, Hasday JD, Taciak V, Broderick K, Viscardi RM
Potential role of interleukin-1 in the development of bronchopulmonary dysplasia.
J Interferon Cytokine Res. 1996; 16: 365-73
Display abstract
Increased activities of inflammatory mediators unopposed by their inhibitors contribute to chronic lung injury and impaired healing in BPD. The deleterious effects of IL-1 beta, a cytokine involved in inflammation and host defense, are blocked by IL-1 receptor antagonist (IL-1Ra). We proposed that an imbalance of IL-1 beta and its inhibitors may contribute to the development of BPD. To determine the relative antigen concentrations of IL-1 beta and IL-1Ra and functional IL-1 activity in lung lavage of infants at risk for BPD, lung lavage was serially obtained from 1 to 28 days from 17 infants with evolving BPD, 13 infants with self-limited RDS, and 6 controls ventilated for nonpulmonary reasons. Overall, there was a high correlation between IL-1 beta antigen concentration and IL-1 activity (r = 0.82, p = 0.0001). There were no significant differences among the groups for lung lavage variables on day 1. However, in infants who developed BPD, IL-1 beta antigen concentration and IL-1 activity increased 16- and 61-fold, respectively, during the first week. IL-1Ra remained relatively unchanged during the first month. IL-1 beta/IL-1Ra antigen ratio was significantly higher on days 5 (median 0.024) and 7 (median 0.025) compared with day 1 (median 0.004), p < 0.05. These results suggest that a relative imbalance of IL-1 beta and IL-1Ra may contribute to prolonged inflammation in BPD.

Akeson AL et al.
AF12198, a novel low molecular weight antagonist, selectively binds the human type I interleukin (IL)-1 receptor and blocks in vivo responses to IL-1.
J Biol Chem. 1996; 271: 30517-23
Display abstract
Interleukin-1 (IL-1) -alpha and -beta are potent regulators of inflammatory responses. The naturally occurring interleukin-1 receptor antagonist (IL-1ra) is effective in vitro and in vivo in modulating biological responses to IL-1. We have previously reported the discovery of IL-1 antagonist peptides from the search of phage display libraries. Further characterization of this group of peptides has led to a 15-mer, AF12198, Ac-FEWTPGWYQJYALPL-NH2 (J represents the unnatural amino acid, 2-azetidine-1-carboxylic acid), with both in vitro and in vivo IL-1 antagonist activity. AF12198 selectively binds the human type I IL-1 receptor but not the human type II receptor or the murine type I receptor. In vitro, AF12198 inhibits IL-1-induced IL-8 production by human dermal fibroblasts with a half-maximal inhibition concentration or IC50 of 25 nM and IL-1-induced intercellular adhesion molecule-1 (ICAM-1) expression by endothelial cells with an IC50 of 9 nM. When given as an intravenous infusion to cynomolgus monkeys, AF12198 blocks ex vivo IL-1 induction of IL-6 and down modulates in vivo induction of IL-6. This is the first small molecule to show IL-1 receptor antagonist activity in vivo.

Akeson A, Bohnke R, Schroeder K, Kastner P, Seligmann B, Robinson J
An ex vivo method for studying inflammation in cynomolgus monkeys: analysis of interleukin-1 receptor antagonist.
J Pharmacol Toxicol Methods. 1996; 36: 155-61
Display abstract
Nonhuman primates have been used as models for testing the role of interleukin-1 (IL-1) in inflammatory diseases, including endotoxemia. The objective of this investigation was to develop a reproducible and rapid method for in vivo evaluation of IL-1 antagonists using cynomolgus monkeys. IL-1 alone can induce many of the symptoms of endotoxemia in monkeys including fever, loss of appetite, and lethargy, however, test animals are slow to recover and may become desensitized to IL-1. We have developed an ex vivo method using whole blood for analysis of IL-1 antagonists administered in vivo to the monkeys and report here results for the naturally occurring IL-1 receptor antagonist, IL-1ra. In this procedure, animals are given an i.v. infusion of IL-1ra, and blood samples are taken preinfusion and during the infusion. The samples are incubated with or without IL-1 beta and the subsequent ex vivo induction of IL-6 determined. This allows analysis of the effects of in vivo pharmacodynamics on the efficacy of antagonists without exposing the test animals to IL-1. In this ex vivo protocol, each animal serves as its own control, eliminating from the assessment the large animal to animal variation observed with in vivo responses. By testing various doses, we estimate that 50% inhibition of IL-1 induced IL-6 can be achieved with an infusion of IL-1ra at 5 micrograms/kg/15 min. This method allows simple and efficient analysis of inhibitors and antagonists of IL-1 and, potentially, other effectors.

Colotta F et al.
Regulated expression and release of the IL-1 decoy receptor in human mononuclear phagocytes.
J Immunol. 1996; 156: 2534-41
Display abstract
The aim of this study was to investigate the expression and release of the IL-1 type II decoy receptor (R) in mononuclear phagocytes, which play a central role in immune and chronic inflammatory reactions. Human monocytes expressed both type I and type II R transcripts, the latter being two- to threefold more represented. By cross-linking and Ab blocking, the predominant surface IL-1-binding molecule was the decoy RII. IL-4, IL-13, and dexamethasone induced RI and RII transcripts and augmented the number of IL-1-binding sites with no modification of Kd values. The induced surface receptor was identified as the decoy RII. These stimuli induced the release of a soluble R with a m.w. of approximately 60 kDa, of which N-glycosylation contributed 22 kDa compared with 45 kDa released from polymorphonuclear leukocytes, of which N-glycosylation contributed 15 kDa. IL-13 and dexamethasone induced a release of 24 ng/ml/2 x 10(7) cells (from 8.7 to 43.2 ng/ml) and 25.6 ng/ml/2 x 10(7) cells (from 9.7 to 36.8 ng/ml) of decoy RII in 18 h, respectively (six donors). Thus, for instance, IL-13-treated (18 h) cells expressed 3.5 x 10(3) sites/cell and released 12 x 10(3) decoy RII/cell. The released decoy RII from monocytes bound IL-1apha and IL-1 receptor antagonist 30- and 2-fold less avidly than IL-1beta, respectively. In vitro-matured, monocyte-derived macrophages showed higher levels of surface expression and release of the IL-1 decoy RII. The results show that, on exposure to diverse molecules with anti-inflammatory properties, mononuclear phagocytes express and release copious amounts of a novel version of the soluble IL-1 decoy RII.

Sarubbi E, Yanofsky SD, Barrett RW, Denaro M
A cell-free, nonisotopic, high-throughput assay for inhibitors of type-I interleukin-1 receptor.
Anal Biochem. 1996; 237: 70-5
Display abstract
A cell-free, nonisotopic assay has been developed to discover molecules that compete with the natural ligands for binding to the active site of the Type-I interleukin-1 receptor. The key reagents are the interleukin-1 receptor antagonist, a recombinant soluble form of the receptor (sIL-1R), and a specific anti-sIL-1R nonneutralizing monoclonal antibody (MAb79). With these molecules a sensitive assay has been developed using a reversed format: the ligand is immobilized and the receptor is in solution. The ligand-bound receptor is detected using MAb79 and an enzyme-linked secondary antibody. Since no cells or cell membranes are used, the assay is very robust, with no interference from membrane-perturbing agents and high resistance to the organic solvents normally used to resuspend compounds of chemical libraries. The microplate format and colorimetric detection have allowed the complete automation of the immobilized-ligand IL-1 receptor binding assay, which has been used for high-throughput screening of synthetic compounds and natural products.

Wehling P, Cleveland SJ, Heininger K, Schulitz KP, Reinecke J, Evans CH
Neurophysiologic changes in lumbar nerve root inflammation in the rat after treatment with cytokine inhibitors. Evidence for a role of interleukin-1.
Spine. 1996; 21: 931-5
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STUDY DESIGN. The present study was designed to evaluate the effect of cytokine inhibitors in experimental allergic radiculitis. OBJECTIVE. Evaluation of the effect of cytokine inhibitors in experimental allergic radiculitis. SUMMARY OF BACKGROUND DATA. A number of cytokines are known to be involved in hyperalgesia and may play a role in radiculitis. Corticosteroids and other cytokine inhibitors antagonize their effects. METHODS. Experimental allergic radiculitis was induced in rats by injection of bovine myelin from the peripheral nervous system. The sham group subsequently received saline injections; the treatment groups received either prednisolone or interleukin-1 receptor antagonist. Treatment effect was assessed on the basis of motor performance and neurophysiologic parameters. RESULTS. Treatment ameliorated the symptoms of experimental allergic radiculitis. Prednisolone appeared to be somewhat more effective than interleukin-1 receptor antagonist. CONCLUSIONS. Because interleukin-1 receptor antagonist specifically blocks the effects of interleukin-1 at its receptors, the present results imply that interleukin-1 is a causal factor in the model of experimental radiculitis used. Its specificity and apparent lack of side effects make interleukin-1 receptor antagonist an attractive candidate treatment for the human disease.

Ilyin SE, Plata-Salaman CR
An approach to study molecular mechanisms involved in cytokine-induced anorexia.
J Neurosci Methods. 1996; 70: 33-8
Display abstract
Cytokines are released during pathophysiological processes. Cytokines (e.g., interleukin-1 beta or IL-1 beta) induce neurological manifestations including anorexia. Here, we show an integrative approach to investigate the cellular and molecular basis of cytokine-induced anorexia. In this approach: (1) the chronic intracerebroventricular (icv) microinfusion (via osmotic minipumps) of cytokines, at doses that will yield estimated pathophysiological concentrations reported in the cerebrospinal fluid, is used. (2) General and computerized behavioral monitoring characterizes the microstructure of behavioral modifications induced by a cytokine, and the time course for cytokine action. (3) Brain regions and subregions (nuclei/areas) from animals exhibiting significant anorexia in response to cytokine(s) are dissected, and RNA and protein are isolated. (4) The profile of cytokine subsystems (ligands, receptors, endogenous inhibitors; for example, IL-1 alpha and beta, IL-1 receptor types I and II, and IL-1 receptor antagonist) is characterized in the same brain samples with polymerase chain reaction, sensitive RNase protection assays and immunoblots. (5) The relationship between changes in cytokine subsystems at the molecular level and cytokine-induced anorexia within an animal is determined, and the general profile is analyzed with statistical methods. This approach is also pertinent to study neurotransmitter and neuropeptide profiles, and cytokine-cytokine, cytokine-neuropeptide and cytokine-neurotransmitter interactions in vivo. The results show that this integrative and novel strategy can be used to study the molecular basis of anorexia and other neurological manifestations (e.g., fever, sleep changes) induced by cytokines.

Dinarello CA
Biologic basis for interleukin-1 in disease.
Blood. 1996; 87: 2095-147
Display abstract
To understand the role of the proinflammatory cytokine interleukin-1 (IL-1) in disease, investigators have studied how production of the different members of the IL-1 family is controlled, the various biologic activities of IL-1, the distinct and various functions of the IL-1 receptor (IL-1R) family, and the complexity of intracellular signaling. Mice deficient in IL-1Beta, IL-1Beta converting enzyme, and IL-1R type I have also been studied. Humans have been injected with IL-1 (either IL-1alpha or IL-1beta) for enhancing bone marrow recovery and for cancer treatment. The IL-1-specific receptor antagonist (IL-1Ra) has also been tested in clinical trials. The topics discussed in this review include production and activities of IL-1 and IL-1Ra molecules, the effects of IL-1 on gene expression, functions of cell-bound and soluble IL-1 receptors, the importance of the IL-1R accessory protein, newly discovered signal transduction pathways, naturally occurring cytokines limiting IL-1 production or activity, the effects of blocking cyclooxygenase and nitric oxide, and the outcomes of IL-1 and IL-1 Ra in human trials. Special attention is paid to IL-1beta converting enzyme and programmed cell death. The roles of IL-1 in hematopoiesis, leukemia, atherosclerosis, and growth of solid tumors are also discussed. This is a lengthy review, with 586 citations chosen to illustrate specific areas of interest rather than a compendium of references. At the end of each section, a short commentary summarizes what the author considers established or controversial topics linking the biology of IL-1 to mechanisms of disease.

Cuddihy RM, Bahn RS
Lack of an association between alleles of interleukin-1 alpha and interleukin-1 receptor antagonist genes and Graves' disease in a North American Caucasian population.
J Clin Endocrinol Metab. 1996; 81: 4476-8
Display abstract
Although an association between the human leukocyte antigen (HLA) allele DR3 and Graves' disease (GD) is well documented, the potential role of non-HLA-linked alleles in susceptibility to GD is an area of active investigation. In an attempt to study the potential role of two non-HLA susceptibility alleles in GD and Graves' ophthalmopathy, we examined 286 North American Caucasian individuals (145 normal controls and 141 individuals with GD) for the presence of the A2 allele of the interleukin-1 (IL-1) receptor antagonist gene. In addition, we examined a subset of this population (83 normal controls and 89 individuals with GD) for a specific polymorphism within exon 5 of the IL-1 alpha gene. We found the A2 allelic frequencies (0.25 and 0.23, respectively) and carriage rates (43% and 41%, respectively) in the two groups to be nearly identical. However, findings in the subgroup of patients with the extrathyroidal manifestations of GD (Graves' ophthalmopathy, pretibial dermopathy, and acropachy) suggested a trend toward a higher prevalence of the A2 allele in patients with more severe disease. The allelic frequency (0.28) and carriage rate (47%) of the IL-1 alpha exon 5 polymorphism in individuals with GD were nearly identical to those of the control population (0.28% and 45%, respectively). In summary, we were unable to demonstrate an association between these alleles and GD in our study population. We conclude that neither the A2 allele of the IL-1 receptor antagonist gene nor the IL-1 alpha exon 5 polymorphism confers increased susceptibility to GD.

Mantovani A, Muzio M, Ghezzi P, Colotta F, Introna M
Negative regulators of the interleukin-1 system: receptor antagonists and a decoy receptor.
Int J Clin Lab Res. 1996; 26: 7-14
Display abstract
The IL-1 system includes 2 agonists, alpha and beta, processing and transport molecules, receptor antagonists, signalling receptor, a decoy receptor and an accessory molecule. Negative pathways of regulation include the antagonists, of which 3 isoforms have been cloned and the type II "decoy" receptor. Molecules that regulate inflammation and immunity coordinatively affect different components of the system. The complexity of the system and the existence of unique pathways of negative regulation, the antagonists and the decoy receptor, emphasize the need for a tight control of the production and action of IL-1.

Chang DM, Chou WY
The production and characterization of a modified recombinant interleukin-1 receptor antagonist.
Immunol Invest. 1996; 25: 355-68
Display abstract
The increasingly complex cytokine network involves both positive and negative regulatory pathways. Natural inhibitors of cytokines are of great importance both as analytical tools and as potential therapeutic agents. Interleukin-1 (IL-1) inhibitory bioactivity including a specific receptor antagonist of IL-I (IL-1ra) has been described both in cultured cell supernatants and in human body fluids. In the current studies, the cDNA of IL-1ra from human monocytes was obtained by the techniques of mRNA isolation and reverse transcription/polymerase chain reaction (RT/PCR). The IL-1ra cDNA/pET-15b was transfected into DE3 cells and the recombinant protein expressed. The purified protein was demonstrated as a single band with molecular mass of 20 KD by SDS-PAGE; it had strong IL-1 inhibitory activity. This IL-1 inhibitor competed with IL-1 for their receptor as assessed by flow cytometer. The existence of this naturally occurring specific cytokine receptor antagonist may lead to a different perspective of the cytokine network. The availability of this recombinant IL-1 receptor antagonist allows us to test its role on the cytokine network, and on possible disease modification.

Abbondanzo SJ, Cullinan EB, McIntyre K, Labow MA, Stewart CL
Reproduction in mice lacking a functional type 1 IL-1 receptor.
Endocrinology. 1996; 137: 3598-601
Display abstract
Growth factors and cytokines have been identified in having critical roles at mediating maternal-fetal interactions during pregnancy, with interleukin-1 being a recently implicated factor. Previous experiments indicated that repeated intraperitoneal injections of the Il-1 receptor antagonist (Il-1Ra), which inhibits binding of interleukin-1 (Il-1) to the type 1 Il-1 receptor (Il-1Rt1) blocks blastocyst implantation in superovulated mice. To gain a greater insight into the role of Il-1 receptor in implantation, we analyzed the reproduction of mice deficient for the Il-1Rt1. Our results show that mice lacking this receptor do not exhibit any profound alterations in their reproduction, apart from a slight reduction in mean litter size. Furthermore, repeated intraperitoneal injections of either IL-1Ra or the monoclonal antibody 35F5, which also blocks ligand binding to the Il-1Rt1, did not affect embryo implantation in either wild type and Il-1 receptor deficient mice.

Yang ZM, Chen DB, Le SP, Harper MJ
Interleukin-1 alpha in the rabbit uterus during early pregnancy.
Early Pregnancy. 1995; 1: 201-5
Display abstract
Immunoreactive (ir) interleukin-1 alpha (IL-alpha) was present in the endometrium and myometrium of the rabbit uterus during early pregnancy. Interleukin-1 alpha was at a high level in endometrial epithelium from days 3 to 6 of pregnancy. A similar level of IL-1 alpha was detected on day 6 of pseudopregnancy. Interleukin-1 alpha declined rapidly on day 7 at both the implantation and non-implantation areas. Our results suggest that IL-1 alpha may play a role in rabbit blastocyst implantation.

King DP, Hay AW, Robinson I, Evans SW
Leucocyte interleukin-1-like activity in the common seal (Phoca vitulina) and grey seal (Halichoerus grypus).
J Comp Pathol. 1995; 113: 253-61
Display abstract
Interleukin-1 (IL-1) is an important cytokine with predominantly proinflammatory activities, which have been characterized in many mammals. This study showed the production of IL-1-like bioactivity by cultured seal leucocytes. Increasing concentrations of lipopolysaccharide (LPS) (0-1 micrograms/ml) stimulated an increase in measurable IL-1-like activity in cell culture supernates. This activity increased for the first 24 h after LPS stimulation and the substance responsible had an apparent molecular weight of 17 kDa on gel filtration, similar to that described for other species. Specificity of the bioassay used was confirmed by blocking the bioactivity with an IL-1 receptor antagonist (IL-1 ra).

Leff JA, Wilke CP, Furman MJ, Bodman ME, Repine JE
Interleukin-1 pretreatment prevents interleukin-1-induced lung leak in rats.
Am J Physiol. 1995; 268: 126-126
Display abstract
We found that rats pretreated with interleukin-1 (IL-1) intraperitoneally did not develop the acute oxidative, neutrophil-dependent lung leak that occurs after administration of IL-1 intratracheally (IL-1-induced tolerance). IL-1-pretreated rats also had increased lung catalase and glucose-6-phosphate dehydrogenase (G6PDH) activity and increased plasma catalase activity compared with sham-pretreated rats. In contrast to reducing lung leak, IL-1 pretreatment did not reduce the numbers of neutrophils that are increased in lung lavages of rats given IL-1 intratracheally. IL-1-induced tolerance to IL-1-mediated lung leak and the associated increases in lung catalase, lung G6PDH, and serum catalase activities were all prevented by treating rats with the IL-1-receptor antagonist or with N-acetyl-L-cysteine, an agent that increases intracellular glutathione levels. Our results indicate that IL-1 pretreatment confers tolerance to IL-1-mediated lung leak without decreasing IL-1-induced increases in lung neutrophils. The possible protective actions of IL-1 should be considered in experiments and clinical trials where IL-1 activity is reduced pharmacologically.

Zieleniewski W, Zieleniewski J, Stepien H
Interleukin-1 beta, but not IL-1 alpha, stimulates cell proliferation in the adrenal cortex.
Cytobios. 1995; 84: 199-204
Display abstract
Endocrine and immune systems are closely interconnected, so the effect of interleukin-1 on adrenal cortex proliferation in vivo was investigated. Interleukin-1 alpha (IL-1 alpha) and IL-1 beta (0.1, 1 and 10 micrograms/kg) were given twice daily alone or in combination with interleukin-1 receptor-antibody (IL-1rAb) to adult male Wistar rats. The cell proliferation ratio was measured by 5-bromo-2'-deoxyuridine (BrdU) incorporation. BrdU-positive cells were counted in entire equatorial sections of the gland, and, in addition, separately for each adrenocortical zone. IL-1 beta (1 and 10 micrograms/kg) enhanced cell growth in the adrenal cortex. This was due to the stimulation of cell proliferation in the zona glomerulosa and fasciculata. IL-1rAb exerted an opposite effect, and reversed the stimulatory influence of IL-1 beta. IL-1 alpha did not evoke any significant changes in the proliferation ratio of the adrenocortical cells. The results indicate a close interconnection between the immune and endocrine systems with IL-1 beta providing a growth-promoting stimulus to adrenocortical cells.

van der Laken CJ et al.
Specific targeting of infectious foci with radioiodinated human recombinant interleukin-1 in an experimental model.
Eur J Nucl Med. 1995; 22: 1249-55
Display abstract
In the present study, radioiodinated human recombinant interleukin-1 (IL-1) was investigated for its potential to image infectious foci in vivo in an animal model of infection. Twenty-four hours after induction of a Staphylococcus aureus abscess in the left calf muscle, mice were i.v. injected with both iodine-125 labelled IL-1 and iodine-131 labelled myoglobin, a size-matched control agent. The animals were killed for tissue biodistribution studies at 2, 6, 12, 24 and 48 h p.i. Gamma camera images were obtained at 6, 24 and 48 h after injecting mice with 123I-IL-1. Radioiodinated IL-1 rapidly cleared from the body; after 12 h the abscess was the organ with the highest activity. The absolute abscess uptake of 125I-IL-1 remained high compared to 131I-myoglobin, resulting in significantly higher abscess-to-muscle ratios of 125I-IL-1 compared to 131I-myoglobin. The ratios of 125I-IL-1 reached the ultimate value of 44.4+/-10.8 at 48 h p.i., whereas the ratios of 131I-myoglobin did not exceed 5.9+/-0.7. Gamma camera imaging revealed clearly visible abscesses. In conclusion, our results demonstrate specific retention of radioiodinated IL-1 in the abscess, presumably by interaction of IL-1 with its receptor on the inflammatory cells. The high target-to-background ratios that were obtained over the course of time indicate that the IL-1 receptor may be a valuable target for the imaging of infectious foci.

Zieleniewski W, Zieleniewski J, Stepien H
Effect of interleukin-1a, IL-1b and IL-1 receptor antibody on the proliferation and steroidogenesis of regenerating rat adrenal cortex.
Exp Clin Endocrinol Diabetes. 1995; 103: 373-7
Display abstract
Several data suggest that the endocrine and immune systems are closely interconnected, therefore, we investigated the effect of interleukin-1 on adrenocortical regeneration. The study was performed on adult rats subjected to left adrenal enucleation combined with contralateral adrenalectomy. The animals were given purified human recombinant IL-1 alpha (5 micrograms/kg), IL-1 beta (5 micrograms/kg) anti-human IL-1 receptor antibody (10 micrograms/kg) and combination of interleukins and antibodies. The cell proliferation measured by bromodeoxyuridine incorporation and plasma corticosterone determined by a RIA kit were evaluated six days after operation. The mean cell growth ratio expressed as number of BrdU-positive cells per 1,000 cells was 11.86 +/- 0.45 in the control group. IL-1b significantly stimulated the proliferation ratio (15.30 +/- 0.88; p < 0.01) and this effect could be prevented by addition of IL-1rAb. The antibody caused also a well-marked inhibition of cell growth ratio (8.23 +/- 0.67; p < 0.01). The plasma corticosterone concentration was higher in IL-1b-treated animals than in the control group, 107.79 +/- 2.82 vs. 61.08 +/- 2.0 ng/ml, respectively, p < 0.01. On the other hand, IL-1rAb decreased corticosterone secretion (31.53 +/- 2.58 ng/ml, p < 0.01) and reversed the stimulatory effect of of IL-1b. In contrast, IL-1a seemed to have no influence on adrenocortical regeneration. In conclusion, this study supported the thesis of close interconnection between immune and endocrine systems and revealed that IL-1b could act as a growth-promoting factor on regenerating adrenal cortex in the rat.

Malinowsky D, Chai Z, Bristulf J, Simoncsits A, Bartfai T
The type I interleukin-1 receptor mediates fever in the rat as shown by interleukin-1 receptor subtype selective ligands.
Neurosci Lett. 1995; 201: 33-6
Display abstract
The interleukin-1 (IL-1) system possesses two distinct receptors (type I and type II) which, together with the accessory protein, mediate a multitude of responses to IL-1 alpha and IL-1 beta, including fever. So far, no receptor subtype-specific ligands have been described. Since both types of IL-1 receptors occur in the thermoregulatory areas it was unclear which IL-1 receptor type mediates fever. We report here that for a series of deletion mutants of human recombinant IL-1 beta (hrIL-1 beta), the affinity of these ligands for the type I IL-1 receptor correlates with their efficacy to evoke the fever response (hrIL-1 beta > des-SND52-54 > des-QGE48-50 > des-I56). Thus, the results suggest that agonist occupancy of the type I IL-1 receptor is essential for IL-1 beta-mediated fever.

Brown D, Sadeghi R, Steel J, Moore M, Gammon G
Detection of interleukin-1 signal transduction inhibitors: action of protein kinase inhibitors.
Int J Immunopharmacol. 1995; 17: 887-94
Display abstract
The dysregulated production of IL-1 has been shown to play an important role in many pathological processes. Despite the apparent value of compounds able to inhibit either the secretion of IL-1 or its signal transduction pathway in a specific manner, there are no such compounds suitable for clinical use. A major problem in identifying novel and specific inhibitors of signal transduction is the lack of knowledge of the intracellular events which mediate the cellular actions of IL-1. In this study a simple cellular assay has been established to screen natural product and synthetic compound libraries for low molecular weight inhibitors of the cytokine signalling pathways of potential therapeutic value. In addition, we have studied the action of several known modulators of signal transduction on the actions of IL-1.

Estrov Z, Kurzrock R, Talpaz M
Interleukin-1 and its inhibitors: implications for disease biology and therapy.
Cancer Treat Res. 1995; 80: 51-82
Display abstract
IL-1 alpha and IL-1 beta are polypeptide hormones that exhibit a broad spectrum of beneficial and harmful biologic activities. Clinical trials designed to benefit from its stimulatory effects on human hematopoiesis and from its role in improving host defenses, are being currently conducted. Other in vivo studies, using IL-1 inhibitors with an attempts to block the detrimental effects of IL-1, are underway. Because of the multifunctional effects of IL-1 in human physiology and its pathogenetic role in several diseases, the capability to control the effects of IL-1 may prove to be a useful tool in medical practice.

Praast G et al.
The internalized interleukin-1 activation complex in fibroblasts localizes to the Golgi apparatus.
J Inflamm. 1995; 46: 125-38
Display abstract
In order to investigate binding and internalization of interleukin-1 (IL-1) by confocal laser scanning microscopy, we established a model system comprising an IL-1 receptor type I (IL-1R1) overexpressing transfectant of the murine fibrosarcoma cell line L929 (L929R1) and an N-terminal FLAG-tagged human recombinant IL-1 alpha (FLAG-IL-1 alpha). The function of the transfected receptors was shown by their IL-1-induced association with a kinase activity. The biological activity of the purified FLAG-IL-1 alpha was comparable to the unmodified molecule. L929RI cells were exposed to saturating concentrations of FLAG-IL-1 alpha. Two-color fluorescence analysis revealed increasing cell surface binding of FLAG-IL-1 alpha to the receptor over 30 min. This was followed by internalization and accumulation of the ligand/receptor complex at the Golgi apparatus. After 3 hr the receptor signal significantly decreased and patches of FLAG-epitopes reappeared on the cell surface, no longer colocalized with IL-1R1. Thus, in this model, the previously assumed nuclear accumulation of IL-1 was not detected but rather localization of the internalized IL-1/IL-1R1-complex to the Golgi apparatus was found. Direct effects of IL-1 on the nucleus or the nuclear membrane therefore are unlikely.

Kupper TS, Groves RW
The interleukin-1 axis and cutaneous inflammation.
J Invest Dermatol. 1995; 105: 6266-6266
Display abstract
Since the discovery that epidermal cell-derived thymocyte-activating factor was identical to interleukin (IL)-1 alpha and -beta in 1986, these molecules have been implicated in the pathogenesis of skin diseases. In 1995, it has become clear that a group of gene products function to regulate the activity of IL-1. IL-1 alpha and mature 17-kD IL-1 beta (cleaved from precursor by IL-1 beta-converting enzyme) bind to the type 1 IL-1 receptor to transduce a signal. This process can be antagonized at the level of the receptor by two distinct forms of the IL-1 receptor antagonist, which bind to the type I receptor but do not transduce a signal. The process can also be antagonized at the level of the ligand by either cell-bound or soluble type 2 IL-1 receptor. This type 2 IL-1 receptor binds ligand but does not transduce a signal. Keratinocytes can make each of these variables in vitro, and the balance between agonists and antagonists dictates the biologic outcome of a putative IL-1-mediated event. Transgenic mice that overexpress each of these factors individually in epidermis will be useful for enhancing our understanding of the cutaneous biology of IL-1.

Ratnoff OD, Voytus JA, Toossi Z
Inhibition of expression of monocyte interleukin-1 by inhibitors of Hageman factor (factor XII).
J Lab Clin Med. 1995; 125: 247-50
Display abstract
In an earlier study, activated species of Hageman factor (factor XII) induced elaboration of interleukin-1 by human monocytes. These observations did not address whether Hageman factor participated in endotoxin-induced release of interleukin-1. To examine this question, the release of interleukin-1 by endotoxin-stimulated human mononuclear cells was measured in the presence of popcorn inhibitor, a specific inhibitor of Hageman factor. In the experiments herein described, popcorn inhibitor sharply decreased the release of interleukin-1 by human mononuclear cells that were incubated with endotoxin. This observation suggests that Hageman factor may play a role in the elaboration of interleukin-1 by human mononuclear cells. Conforming with this view, the addition of antiserum directed against Hageman factor inhibited the release of interleukin-1 from endotoxin-stimulated mononuclear cells.

Haour F, Marquette C, Ban E, Crumeyrolle-Arias M, Fillion G
[Interleukin-1 receptors in the central nervous system: role in infection and in stress]
J Psychiatry Neurosci. 1995; 20: 357-63

Estrov Z et al.
Effect of interleukin-1 beta converting enzyme inhibitor on acute myelogenous leukemia progenitor proliferation.
Blood. 1995; 86: 4594-602
Display abstract
Interleukin-1 beta (IL-1 beta) converting enzyme (ICE) is a cysteine protease that specifically cleaves precursor IL-1 beta to its biologically active form. Recent studies have also implicated ICE in the induction of apoptosis in vertebrate cells. Because IL-1 plays a major role in acute myelogenous leukemia (AML) blast proliferation, we sought to investigate the effect of ICE inhibition on AML progenitors. To do this, we used bocaspartyl (benzyl) chloromethylketone (BACMK) an inhibitor designed to penetrate cells and bind covalently to the active site of ICE. Our preliminary experiments showed that incubation of activated peripheral blood cells with 2.5 mumol/L of BAMCK downregulated production of mature IL-1 beta but had no effect on tumor necrosis factor-alpha. To test the effects of the inhibitor on AML cells, we first used the OCI/AML3 cell line. We found that these cells produce IL-1 beta and bind the biotinylated cytokine and that IL-1 inhibitors, such as IL-1 neutralizing antibodies, IL-1 receptor antagonist, and soluble IL-1 receptors, specifically inhibit OCI/AML3 proliferation, indicating that IL-1 beta is an autocrine growth factor for OCI/AML3 cells. The ICE inhibitor suppressed OCI/AML3 growth in a dose-dependent manner (at 0.4 to 4 mumol/L) and downregulated mature IL-1 beta production, as assessed by Western immunoblotting. Similar results were obtained with marrow aspirates from 16 AML patients. The ICE inhibitor suppressed proliferation of AML precursors (by up to 78%; mean, 44%) in a dose-dependent fashion at concentrations ranging from 0.4 to 5 mumol/L but not proliferation of normal marrow progenitors; the suppressive effect was reversed by IL-1 beta. Furthermore, incubation of AML cells with 4 mumol/L BAMCK downregulated the production of mature IL-1 beta, suggesting that the growth-inhibitory effect is mediated through suppression of the biologically active cytokine. Our data indicate that inhibition of ICE suppresses AML blast proliferation and suggest that ICE inhibitors may have a role in future therapies for AML.

Fischer SM, Lee WY, Locniskar MF
The pro-inflammatory and hyperplasiogenic action of interleukin-1 alpha in mouse skin.
Prog Clin Biol Res. 1995; 391: 161-77

Robak T
[Biological properties and clinical importance of interleukin 1]
Postepy Hig Med Dosw. 1995; 49: 263-85
Display abstract
The paper presents the molecular biology and biological activity of IL-1 alpha, IL-1 beta and IL-1 receptor antagonist. The role of IL-1 family in pathogenesis of a various disease including myeloid leukemias and other neoplastic diseases, diabetes mellitus, inflammatory diseases, sepsis syndrome and atherosclerosis is presented. Potential therapeutic value of IL-1 and IL-1 receptor antagonist is also discussed.

Dower S
Interleukins.
Adv Dent Res. 1995; 9: 19-19

Quan N, Sundar SK, Weiss JM
Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide.
J Neuroimmunol. 1994; 49: 125-34
Display abstract
The presence of bioactive interleukin-1 (IL-1) in various brain regions (cerebellum, cortex, brainstem, diencephalon or hippocampus) after either intraperitoneal (i.p.) or intraventricular (i.c.v.) injection of lipopolysaccharide (LPS) was studied in the rat. To detect IL-1, extracellular fluid and cell lysate were fractionated by gel exclusion chromatography and fractions tested for thymocyte stimulation; presence of IL-1 was confirmed by blockade of stimulation by addition to the assay of a monoclonal antibody (mAb) to IL-1 receptor. When LPS was infused i.c.v., IL-1 was detected in the brainstem and diencephalon 2 h after injection, and in all the brain regions except cerebellum 6 h after injection; IL-1 was not detected in the plasma of these animals. When LPS was injected i.p., IL-1 was detected in the plasma but not in the brain 2 h after the injection, and in all brain regions but not in the plasma 6 h after the injection. In all of these cases, IL-1 was found in extracellular fluid; in some cases (cortex, cerebellum) cell lysate of the region did not produce detectable bioactivity, thereby indicating that IL-1 in these brain regions is processed to active peptide during release, as has been reported in the periphery. In those cases where bioactivity was detected in cell lysate (brainstem, diencephalon), bioactivity was not blocked by IL-1 receptor mAb, indicating presence of a non-IL-1 stimulating factor. These results further support the idea that IL-1 is secreted by cells in the brain, and indicate that it is found in the extracellular fluid of many brain regions following an appropriate stimulus in the periphery as well as in the brain.

Guidot D, Repine JE
Interleukin-1-induced tolerance to IL-1-induced oxidative lung injury in rats.
Chest. 1994; 105: 86-86

Rothwell NJ, Luheshi G
Pharmacology of interleukin-1 actions in the brain.
Adv Pharmacol. 1994; 25: 1-20

Dinarello CA
Interleukin-1 antagonists.
J Interferon Res. 1994; 14: 307-307

Mori N, Shirakawa F, Murakami S, Oda S, Eto S
Interleukin-1 alpha as an autocrine growth factor for acute lymphoblastic leukaemia cells.
Br J Haematol. 1994; 86: 386-8
Display abstract
We describe a case of B-lineage acute lymphoblastic leukaemia (ALL) with proliferation of leukaemic cells through an interleukin-1 alpha (IL-1 alpha) autocrine mechanism. Flow cytometric analysis using the IL-1 receptor type II (IL-1Rt II) monoclonal antibody (mAb) demonstrated the expression of the IL-1Rt II on leukaemic cells: this is the first report in IL-1RtII-positive freshly isolated ALL cells from a patient. In accordance with the expression of IL-1RtII, the leukaemic cells proliferated in response to exogenous IL-1 alpha. In addition, anti-IL-1 alpha mAb markedly inhibited the spontaneous cell proliferation. Furthermore, Northern blot analysis detected IL-1 alpha mRNA without any stimulation. These observations suggest that IL-1 alpha may play an important role as an autocrine growth factor in some cases of ALL.

Sims JE, Giri JG, Dower SK
The two interleukin-1 receptors play different roles in IL-1 actions.
Clin Immunol Immunopathol. 1994; 72: 9-14
Display abstract
The proinflammatory cytokine interleukin-1 binds to two cell-surface receptors. The type I receptor, an 80-kDa protein with a cytoplasmic domain of approximately 215 amino acids, mediates the biological effects of IL-1. The type II receptor, a 60-kDa protein with 29 cytoplasmic amino acids, binds IL-1 and thereby prevents it from binding to the type I receptor but does not deliver a biological signal. Thus, the type II receptor acts as a negative regulator of IL-1 actions. It can do so either as a membrane-bound molecule or subsequent to shedding from the cell surface to generate a so-called "soluble" receptor. Both the naturally produced soluble type II receptor and the recombinantly generated soluble type I receptor are effective inhibitors of IL-1 action. The soluble type I receptor has shown efficacy in some preclinical models of inflammatory diseases, as well as in an initial clinical trial in a setting of cutaneous allergy.

Simon C, Frances A, Piquette G, Hendrickson M, Milki A, Polan ML
Interleukin-1 system in the materno-trophoblast unit in human implantation: immunohistochemical evidence for autocrine/paracrine function.
J Clin Endocrinol Metab. 1994; 78: 847-54
Display abstract
Interleukin-1 receptor type I, IL-1 beta, IL-1 receptor antagonist, and human macrophages were immunohistochemically localized in the villous trophoblast, maternal-trophoblast interphase, and maternal decidua during early human implantation. Immunostaining for IL-1 receptor type I was present in the syncytiotrophoblast and hyperplastic endometrial glands in the maternal decidua. Immunoreactive IL-1 beta was present in the villous cytotrophoblast, syncytiotrophoblast, intermediate trophoblast, and maternal stromal decidual cells. IL-1 receptor antagonist staining was observed in the glandular endometrium of the maternal decidua and in isolated cells located inside the chorionic villi, intervillous space, and maternal decidua. Mature human macrophages, as defined by both CD/68+ and HAM56+, were present in the chorionic villi, maternal blood of intervillous space, and maternal decidua. Co-localization studies demonstrated that macrophages in all of the reported locations also stained for immunoreactive IL-1 beta. Our results show the shared presence in maternal and embryonic tissues of this receptor-agonist-antagonist system during early human implantation. This finding supports an autocrine/paracrine role for the IL-1 system in human implantation.

Sims JE, Dower SK
Interleukin-1 receptors.
Eur Cytokine Netw. 1994; 5: 539-46

Baldassano RN
Do bacterial cell wall polymers perpetuate chronic intestinal inflammation in the susceptible host?--role of cytokines.
J Pediatr Gastroenterol Nutr. 1994; 19: 474-5

Alnaif B, Benzie RJ, Gibb W
Studies on the action of interleukin-1 on term human fetal membranes and decidua.
Can J Physiol Pharmacol. 1994; 72: 133-9
Display abstract
Recent studies have indicated the possible importance of cytokines in the onset of term and preterm labor. To examine this further, the effect of interleukin-1 beta (IL-1 beta), interleukin-1 alpha (IL-1 alpha), and interleukin-6 (IL-6) on prostaglandin output by dispersed cells from human amnion, chorion laeve, and decidua obtained at term (38-40 weeks gestation) was examined. During the first or second 24 h of culture no significant effect of these interleukins on prostaglandin output was observed. The reason for this apparent refractoriness was further investigated by studying the distribution of IL-1 receptors in frozen sections of undisrupted fetal membranes and decidua at term. Whole-tissue autoradiography indicated that receptors were present in chorion-decidua but not in amnion. By using emulsion autoradiography, IL-1 receptors were found in high concentrations in chorion laeve and were absent in amnion and at low levels in the decidua. These studies indicate that under normal circumstances in human pregnancy at term IL-1 did not stimulate prostaglandin production by dispersed cells. In the case of amnion, this may be due to the absence of receptors, and therefore it would appear that the IL-1 receptor must first be induced in this tissue before it can respond to this cytokine. Furthermore, although chorion laeve expresses the IL-1 receptor, dispersed cells from this tissue did not respond to the cytokine by increasing prostaglandin output.

Wustrow TP
Biology of interleukin-1 (IL-1), with respect to otorhinolaryngology-head and neck surgery.
Head Neck. 1994; 16: 88-94
Display abstract
Interleukin-1 (IL-1) has a number of fundamental immunoregulatory, hematologic, metabolic, and physiologic effects and thus is instrumental in the coordination of tissue interactions, such as wound healing, inflammation, and host tumor response. IL-1 stimulates the activation and differentiation of pre-B cells and T cells, chemotaxis of neutrophils, recruitment of bone marrow stem cells, stimulation of arachidonic acid metabolism, degradation of proteoglycans, and increase in basal body temperature. Altered production of IL-1 or IL-1 regulatory factors may have profound clinical consequences, such as seen in AIDS, other viral and malignant diseases, and in uncontrolled inflammatory processes. A variety of positive and negative feedback mechanisms for regulation of IL-1 production have been found; therapeutic interventions are aimed at these regulatory pathways. Through approaches interfering with the signal transduction or processing of IL-1, especially by interleukin-1-receptor antagonists (IL-1RA), future treatment modalities are on the horizon.

Dinarello CA
Interleukin-1 in disease.
Keio J Med. 1994; 43: 131-6
Display abstract
As outlined in this review, the inflammatory cytokine interleukin-1 (IL-1) mediates a number of pathological processes associated with disease. To prove a role for IL-1, a variety of modalities have been used to block the production and/or activity of IL-1. These include agents which inhibit or reduce 1) IL-1 transcription and/or synthesis, 2) the processing of pro-IL-1 beta into its mature forms, 3) the secretion of IL-1 beta, 4) the activity of IL-1 using neutralizing anti-IL-1 antibodies or 5) soluble (extracellular) IL-1 receptors, 6) the ability of IL-1 to bind to its receptors using receptor blockade, 7) the availability of surface receptors using agents which down-regulate receptor expression or (8) agents which affect IL-1-mediated signal transduction. Some of these modalities have already entered clinical trials. Clearly, the therapeutic advantage of reducing the activity of IL-1 resides in preventing its deleterious biological effects without interfering with host defense and homeostasis. For example, blocking IL-1-induced prostaglandins is one target in treating inflammatory diseases. Drugs inhibiting cyclooxygenase have well-known toxicities because they block the normal physiologic synthesis of prostaglandins in many tissues such as platelets and gastric lining cells. Blocking IL-1, in contrast, reduces only that portion of prostaglandin synthesis due to elevated IL-1, sparing the synthesis of prostaglandins necessary for physiologic homeostasis. A similar case can be made for endogenous nitric oxide. Thus, there is a unique pharmacological advantage to blocking IL-1 in disease.

Martin M, Bol GF, Eriksson A, Resch K, Brigelius-Flohe R
Interleukin-1-induced activation of a protein kinase co-precipitating with the type I interleukin-1 receptor in T cells.
Eur J Immunol. 1994; 24: 1566-71
Display abstract
We have investigated the possibility of a protein kinase participating in the signal transduction mechanisms of the interleukin-1 (IL-1) type I receptor (IL-1RI). Our data show that a protein kinase was co-precipitated with the IL-1RI from the two murine T helper cell lines D10N and EL-4. The kinase activity was detected in an in vitro kinase assay performed with the immuno beads in the presence of exogenous substrates. IL-1 treatment of the cells resulted in a rapid activation of this protein kinase in a concentration-dependent manner. Both forms of IL-1, IL-1 alpha and IL-1 beta, induced this kinase activity, whereas the IL-1 receptor antagonist (IL-1ra) was inactive. In excess IL-1ra competitively antagonized IL-1 stimulation. In the in vitro kinase assay the exogenous substrates myelin basic protein and histone H1 were phosphorylated, whereas casein or heat-shock protein HSP27 were not accepted, reflecting a certain selectivity of this protein kinase. The IL-1RI co-precipitable protein kinase showed a serine/threonine specificity and was inhibited by staurosporine, but not by inhibitors specific for protein tyrosine kinase or protein kinase C. These results show that a serine/threonine protein kinase directly interacts with the IL-1RI at the plasma membrane level of T helper cells forming a novel type of IL-1 inducible signaling complex. This protein kinase may resemble the link coupling the plasma membrane IL-1 receptor to cytosolic downstream elements in the IL-1 signaling pathway.

Kulkarni PS, Bhattacherjee P, Paterson CA
Dexamethasone inhibits interleukin-1 release in endotoxin-uveitis model.
Exp Eye Res. 1994; 58: 637-8

Weiss JM, Quan N, Sundar SK
Widespread activation and consequences of interleukin-1 in the brain.
Ann N Y Acad Sci. 1994; 741: 338-57
Display abstract
The results described herein indicate that elevation of IL-1 in rat brain, either by infusion of IL-1 into the brain or by stimulation of release of endogenous IL-1 in the brain by LPS, rapidly suppresses a variety of immune responses measured in peripheral lymphocytes. This effect can be blocked by infusion of alpha-MSH into brain, an attribute that was used to indicate that the effects of LPS infusion occurred by stimulation of endogenous IL-1 and not some other influence of LPS. That suppression of cellular immune responses indeed describes the consequences of elevating IL-1 in brain was shown by determining the time course of effects and thereby demonstrating that rebound enhancement of cellular immune responses did not occur after either IL-1 or LPS. Studies that examined the mechanisms by which brain IL-1 affects immune responses indicated that IL-1 influences peripheral lymphocytes by stimulation of CRF in the central nervous system and that CRF in turn causes suppression of cellular immune responses through activation of both the pituitary-adrenal axis and the autonomic nervous system. These findings have also been observed in another laboratory. Moreover, Brown et al. have shown that IL-1 in brain suppresses macrophage function in addition to the suppression of lymphocyte functions described herein. The physiologic significance of IL-1 actions in the brain on immune responses remains to be determined, but the demonstration that this cytokine influences immune processes by acting in brain opens for study another means by which brain and immune system interact.

Yang TB
[The regulatory network of interleukin 1 in vivo]
Sheng Li Ke Xue Jin Zhan. 1994; 25: 309-13

Espat NJ, Rogy MA, Copeland EM, Moldawer LL
CMNSG Guest Lecture. Interleukin-1, interleukin-1 receptor, and interleukin-1 receptor antagonist.
Proc Nutr Soc. 1994; 53: 393-400

Herbelin A, Elhadad S, Ouaaz F, de Groote D, Descamps-Latscha B
Soluble CD23 potentiates interleukin-1-induced secretion of interleukin-6 and interleukin-1 receptor antagonist by human monocytes.
Eur J Immunol. 1994; 24: 1869-73
Display abstract
The low-affinity receptor for IgE (CD23) is cleaved into biologically active soluble fragments (sCD23), some of which have been reported to exhibit pleiotropic activities. However, it is not known whether the sCD23 fragments contribute to the induction and/or regulation of pro-inflammatory cytokine production. In this study, this possibility was tested using interleukin (IL)-1-stimulated human whole blood as an ex vivo model of cytokine cascade production. We show that human recombinant 25-kDa sCD23 significantly enhanced the production of IL-6 in whole blood stimulated by IL-1, but had only little or no effect in the absence of IL-1. The potentiating effect of sCD23 was concentration dependent within the range of plasma levels occurring during various inflammatory processes in man. These results prompted us to study whether sCD23 and IL-1 together also enhance the production of regulating factors exhibiting anti-cytokine activities. Our data indicate that sCD23 augments the release of IL-1 receptor antagonist induced by IL-1. Finally, examining the effect of sCD23 on human peripheral monocytes stimulated by IL-1, we confirmed the capacity of sCD23 to potentiate cytokine production. We suggest that sCD23 can modulate monocyte functions, thereby contributing to the amplification and regulation of immune and inflammatory processes.

Handwerger S
A critical role for interleukin-1 (IL-1) and the type 1 IL-1 receptor in blastocyst implantation.
Endocrinology. 1994; 134: 519-20

Dantzer R
[Neurotropic effects of cytokines: at the limits of immunology and neurobiology]
Pathol Biol (Paris). 1994; 42: 826-9

Evans CH, Robbins PD
The interleukin-1 receptor antagonist and its delivery by gene transfer.
Receptor. 1994; 4: 9-15
Display abstract
The interleukin-1 receptor antagonist (IL-1ra or IRAP) is a small, acidic glycoprotein that competitively inhibits the biological activities of interleukin-1 (IL-1). Alternative splicing gives rise to secreted and intracellular forms of IL-1ra. Both forms block cellular responses to IL-1 by occupying IL-1 receptors without triggering an agonist response. The affinity of IL-1ra for the type I IL-1 receptor is approximately that of IL-1. However, because of IL-1's pronounced "spare receptor" effect, IL-1ra is a weak inhibitor of biological responses to IL-1. The value for the affinity constant of IL-1ra's binding to the type II IL-1 receptor has been the subject of disagreement. However, recent data suggest that human IL-1ra has only weak affinity for the human type II receptor. This is consistent with the likelihood that the type II receptor plays no role in signal transduction, instead being a "decoy" that can be shed as a soluble receptor with the ability bind, and thus inhibit, IL-1. Under the name Antril, IL-1ra is being tested in clinical trials of a number of human diseases where IL-1 plays a major pathophysiologic role. These diseases include sepsis, rheumatoid arthritis, chronic myelogenous leukemia, and asthma, among others. Although IL-1ra has clear pharmacologic potential in such conditions, its application in chronic diseases is limited by difficulties associated with delivering proteins as drugs. As an alternative, we have suggested transfer of the gene coding for IL-1ra; strategies for both local and systemic gene delivery are being developed.(ABSTRACT TRUNCATED AT 250 WORDS)

Dinarello CA
Blocking interleukin-1 receptors.
Int J Clin Lab Res. 1994; 24: 61-79
Display abstract
During inflammation, injury, immunological challenge or infection, interleukin-1 appears to mediate, in part, the pathogenesis, of disease. Most studies on interleukin-1 are derived from experiments in which bacterial products, such as endotoxins from Gram-negative bacteria or exotoxins from Gram-positive organisms, are used to stimulate macrophagic cells. In general, several cytokines are induced by microbes to their products. Although cytokines are thought to play a role in the outcome of disease, only a few have been directly implicated as mediators of the pathogenic mechanisms of the host. Studies on specific inhibition of interleukin-1 activity have employed interleukin-1 receptor antagonist, interleukin-1 receptor blocking antibodies or soluble interleukin-1 receptors. Experiments in vitro, in animal models of disease and in human subjects have shed considerable light on a critical role for interleukin-1 in the pathogenesis of disease. This review focuses on interleukin-1 as a cytokine of strategic importance to the outcome of disease, particularly inflammatory and infectious diseases.

Colotta F, Dower SK, Sims JE, Mantovani A
The type II 'decoy' receptor: a novel regulatory pathway for interleukin 1.
Immunol Today. 1994; 15: 562-6
Display abstract
The interleukin 1 (IL-1) system plays a central role in inflammation and immunity. Of the two receptors that bind IL-1, the type I receptor is known to mediate signaling activity, whereas the function of the type II receptor remains unknown. Here, Francesco Colotta and colleagues review the properties of these receptors and summarize evidence indicating that the type II receptor acts as a regulated decoy target for IL-1.

Dinarello CA
Is there a role for interleukin-1 blockade in intravenous immunoglobulin therapy?
Immunol Rev. 1994; 139: 173-88

Nicklin MJ, Weith A, Duff GW
A physical map of the region encompassing the human interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist genes.
Genomics. 1994; 19: 382-4
Display abstract
We have constructed a restriction map of the human genomic region containing the genes encoding the three members of the interleukin-1 (IL-1) family, IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist (IL-1 ra). For this purpose, pulsed-field gel electrophoresis blots were hybridized with probes derived from the three genes. The genes (IL1A, IL1B, and IL1RN, respectively) were found to map to a common restriction fragment of approximately 430 kb that is flanked by two clusters of sites for methylation-sensitive rare-cutter restriction enzymes (putative CpG islands). A likely third internal CpG island was marked by two rare-cutter sites. CpG and non-CpG-specific enzymes were used to map the three genes. Relative to one terminal CpG island, the three genes were mapped to the following intervals: IL1A was between +0 and +35 kb, IL1B was between +70 and +110 kb, and IL1RN was between +330 and +430 kb.

Dower SK, Fanslow W, Jacobs C, Waugh S, Sims JE, Widmer MB
Interleukin-I antagonists.
Ther Immunol. 1994; 1: 113-22

Kagnoff MF
A question of balance: ups and downs of mucosal inflammation.
J Clin Invest. 1994; 94: 1-1

Dinarello CA
The interleukin-1 family: 10 years of discovery.
FASEB J. 1994; 8: 1314-25
Display abstract
Ten years ago the cloning of two interleukin-1 molecules (IL-1 alpha and IL-1 beta) resolved the question of whether a single polypeptide could evoke a wide variety of biological effects. During the past decade, the biology of IL-1 has greatly expanded our understanding of how the host responds to external challenges, such as injury and infection, as well as its role in several diseases. We learned of the remarkable potency of IL-1 in the femtomolar range and of its ability to induce a response by triggering only one or two receptors per cell. Unexpectedly, the IL-1 family of genes, receptors and associated molecules have been linked to those of Drosophila, nematodes, and microorganisms and IL-1 signal transduction is similar to that observed after cellular stress. The cloning of IL-1 opened other avenues of fundamental biological interest. For example, in addition to the two agonist molecules IL-1 alpha and IL-1 beta, a third member of the IL-1 gene family is a specific, high affinity receptor antagonist (IL-1 receptor antagonist). That this third member of the IL-1 family inhibits the other two is characteristic of the tight control over production and activity exerted on IL-1. Although IL-1 contributes to the pathogenesis of many diseases, a small amount appears to be needed to combat infection and initiate healing processes. This article highlights 10 years of discoveries on IL-1.

Guinet F et al.
Interleukin-1 beta-specific partial agonists defined by site-directed mutagenesis studies.
Eur J Biochem. 1993; 211: 583-90
Display abstract
Monocyte-derived interleukin 1 (IL-1) mediates a wide range of biological effects including destruction of the cartilage matrix in articular diseases such as rheumatoid and osteoarthritis. To elucidate further the relationships between protein structure and biological activities, we have analyzed the sequence of several IL-1 polypeptides using the algorithm of Parker, the hydrophobic cluster analysis method and published structural data. This led us to identify several residues that seemed to be strictly topologically conserved, with respect to identifiable secondary structures features, although this was not readily apparent from sequence alignments. We performed site-directed mutagenesis on some of these conserved residues, as well as on those predicted to occur in external loops of the polypeptide. Human IL-1 beta mutant polypeptides were expressed in Escherichia coli in soluble form and purified to homogeneity by anion-exchange and gel-filtration chromatography. Their biological effects (binding to EL4-6.1 murine thymocytes, Raji human B cells and rabbit chondrocytes cells, lymphocyte activation, neutral protease induction, proteoglycan degradation and synthesis) have been determined. Among the 20 IL-1 beta mutant polypeptides we present here, four showed a markedly reduced activity in cartilage matrix assays without any significant change in their binding to the cartilage matrix cells (chondrocytes). Furthermore, some of these mutants were specific partial agonists of the effects of IL-1 on connective tissue since they have a low affinity for thymocytes.

Keppel WH, Regan DH, Heffeneider SH, McCoy S, Ramsey F
Effects of behavioral stimuli on plasma interleukin-1 activity in humans at rest.
J Clin Psychol. 1993; 49: 777-89
Display abstract
Interleukin-1 (IL-1) bioassays were done on 208 serum samples drawn from 7 volunteers, over several hours at 5-minute intervals, before, during, and after a relaxation-related behavioral stimulus. Individuals showed up to a 267% increase (t[29] = 7.750, p = 1 x 10(-7).) in IL-1, and for the group, a mean 48.1% elevation (t[5] = 4.128, p = .003) occurred, during the stimulus interval relative to baseline. When baselines were repeated, IL-1 activity rapidly returned toward baseline values. Suggestions to picture one's immune cells fighting illness appeared to have no uniform effect for all subjects. Such rapid changes in plasma IL-1, concomitant with stimuli, indicate a new way to alter immune function and further understand disease susceptibility.

Johnson CS
Interleukin-1: therapeutic potential for solid tumors.
Cancer Invest. 1993; 11: 600-8

Slack J et al.
Independent binding of interleukin-1 alpha and interleukin-1 beta to type I and type II interleukin-1 receptors.
J Biol Chem. 1993; 268: 2513-24
Display abstract
Interleukin (IL)-1 refers to a group of three polypeptide hormones with a wide range of cellular targets. Two types of IL-1 receptor have been identified and characterized by cDNA cloning. Both human type I and type II IL-1 receptors contain extracellular domains of approximately 310 residues and a single membrane-spanning region. The type I receptor contains a cytoplasmic domain of 213 residues. The cytoplasmic region of the type II receptor is 29 residues in length. It has been found recently that a number of cells express both forms of receptor. By analogy with other cytokine receptor systems, the two IL-1 receptors might be expected to form a heterodimeric complex, the type II receptor being an alpha-chain-like structure, functioning only to bind ligand, and associating with the type I receptor (a beta-chain-like structure) which would transduce signals. In this report we show that this is not the case, but rather that IL-1, when complexed to type II receptor, cannot bind type I receptors, and vice versa. These data show that the complex patterns often observed for IL-1 binding to cells cannot be accounted for by the same type of mechanism that underlies the behavior of, for example, the IL-2 system.

Strassmann G, Masui Y, Chizzonite R, Fong M
Mechanisms of experimental cancer cachexia. Local involvement of IL-1 in colon-26 tumor.
J Immunol. 1993; 150: 2341-5
Display abstract
In the colon-26 (C-26) tumor model, the cytokine IL-6 is an important factor involved in experimental cancer cachexia. Recent in vitro data indicated that IL-1 plays a role in the interaction between host macrophages and C-26 cells that express IL-1R, resulting in the amplification of tumor IL-6 production. To investigate the role of IL-1 on the development of C-26 cachexia in vivo, the effect of specific blockade of the action of IL-1 with reagents against IL-1R was evaluated. Both IL-1R antagonist (IL-1RA) and the mAb 35F5 directed against IL-1R type I, prevented binding of radioactive IL-1, and inhibited IL-1-induced IL-6 synthesis by the C-26 cell line. Whereas a systemic administration of these reagents did not reverse weight loss in C-26-bearing mice, intratumoral injections of IL-1RA significantly reduced cachexia. Furthermore, body composition analysis confirmed that this treatment improved lean tissue and fat, as well as hypoglycemia and serum IL-6 level. The fact that the treatment did not change the tumor burden suggests that it affected the host directly. These results support the hypothesis that, at the microenvironment of the C-26 tumor, IL-1 is involved in the cachexia endured by the host.

Mitchell MD, Edwin SS, Silver RM, Romero RJ
Potential agonist action of the interleukin-1 receptor antagonist protein: implications for treatment of women.
J Clin Endocrinol Metab. 1993; 76: 1386-8
Display abstract
The interleukin-1 receptor antagonist protein (IRAP) caused a concentration-related increase in prostaglandin production by human decidual cells. The degree and time course of this stimulatory action were identical to those induced by interleukin 1 beta (IL-1 beta). IRAP had no inhibitory action on IL-1 beta stimulation of decidual prostaglandin production and at high concentrations had an additive effect. We believe that this represents the first description of a potential agonist action of IRAP and suggests caution in treatment of women with this substance.

Wolfson AJ et al.
Modularity of protein function: chimeric interleukin 1 beta s containing specific protease inhibitor loops retain function of both molecules.
Biochemistry. 1993; 32: 5327-31
Display abstract
Although it is widely recognized that many proteins contain discrete functional domains, it is less certain whether smaller, less obviously discrete, units of structure will retain their specific function when transplanted into a different context. The observation that the potent inflammatory cytokine human interleukin 1 beta has the same overall structure as soybean trypsin inhibitor (STI) (Kunitz) prompted us to replace a tight turn in the cytokine sequence with the large loop in soybean trypsin inhibitor that binds to the active site of trypsin. Wild-type interleukin 1 beta (IL-1 beta) is highly resistant to proteolysis, but the chimeric STI/IL is specifically cleaved by trypsin, apparently in the inserted loop. Other chimeric interleukins have also been constructed, by replacing the same tight turn with inhibitory loops from other protein protease inhibitors: turkey ovomucoid inhibitor (TOI), a chymotrypsin inhibitor, and alpha 1-antitrypsin (AT), an elastase inhibitor. Although these loops come from proteins not related structurally to interleukin 1, they confer specific protease sensitivity or inhibition on the chimeric cytokine. The cytokine properties of these chimeric interleukins have also been evaluated. The chimeras formed from human IL-1 beta and all inhibitory loops tested bind to the interleukin 1 receptor with reasonable affinity. The typical cellular effects of IL-1, however, are not observed with all the recombinant proteins, thus confirming that receptor binding and signal transduction can be uncoupled. When these results are taken together with the results of site-directed mutagenesis of IL-1, reported in this paper and elsewhere, they allow the receptor and intracellular transduction sites on the protein to be mapped in detail.

Yui S, Yang D, Yamazaki M
Heat stable interleukin-1 activity and activity inhibiting thymocyte proliferation in inflammatory polymorphonuclear leukocytes.
Biol Pharm Bull. 1993; 16: 1150-5
Display abstract
The present study demonstrates the co-existence of heat stable interleukin-1 (IL-1) and IL-1-suppressing activity in murine inflammatory polymorphonuclear leukocytes (PMNs). When the IL-1 activity in casein-induced PMN lysate was examined by lymphocyte activating factor assay, it peaked at a concentration of 2.5 x 10(6) cells per ml, but this activity was reduced to nothing at higher concentrations, suggesting the co-existence of IL-1 and IL-1-suppressive factors in PMNs. Although IL-1 has been reported to be inactivated by heat treatment, approximately one-fourth of the IL-1 activity was restored after treatment at 100 degrees C for 10 min. In gel chromatography, the IL-1 activity of the PMN-soluble fraction was eluted in two broad peaks with apparent molecular sizes of 17-23 kDa and 23-43 kDa, respectively. Since the heat stable IL-1 activity was mainly eluted in fractions corresponding to the latter peak, and was neutralized by IL-1 receptor antagonist (IL-1ra) or anti-IL-1 alpha antiserum, the heat stable IL-1 is suggested to be precursor form IL-1 alpha. A high concentration of soluble fraction from PMN lysate, in contrast, completely suppressed the activity of recombinant IL-1 alpha or beta, and the suppressive activity was heat labile. Since thymocyte mitogenesis by 5 micrograms/ml of concanavalin A (Con A) with or without IL-2 was also completely suppressed, the suppressive factor(s) may not be IL-1ra or transforming growth factor beta which were reported to be present in PMNs.

Monti E, Mimnaugh EG, Sinha BK
Synergistic antiproliferative effects of interleukin-1 alpha and doxorubicin against the human ovarian carcinoma cell line (NIH:OVCAR-3).
Biochem Pharmacol. 1993; 45: 2099-107
Display abstract
Interleukin-1 alpha (IL-1 alpha) exerts antiproliferative effects on a human ovarian carcinoma cell line, NIH:OVCAR-3, which is resistant to clinically relevant concentrations of doxorubicin (DOX) and other chemotherapeutic agents. This action of IL-1 alpha depends on the presence of type I (80 kDa) receptors, although no quantitative relationship has been established between receptor occupancy and inhibition of cell growth. When NIH:OVCAR-3 cells were exposed to IL-1 alpha and DOX in combination, a mutual potentiation of the antiproliferative effects of the two agents was observed. This synergistic effect was not due to IL-1 receptor expression up-regulation by DOX, and receptor-dependent internalization of the cytokine was also unaffected. The involvement of IL-1 receptors is supported by the observation that synergism between the two agents was diminished (but not abolished) in the presence of a specific IL-1 receptor antagonist at concentrations blocking more than 75% of IL-1 alpha binding. DOX was found to significantly increase IL-1 alpha accumulation by NIH:OVCAR-3 cells after long-term (48 hr) exposure to the cytokine at 37 degrees, which might be due to increased nonspecific fluid phase uptake or to interference with cytokine degradation and/or release processes. The potent synergy of IL-1 alpha and DOX against ovarian carcinoma cells in vitro suggests that this drug combination may be effective against this disease in the clinic.

Tian ZG, Yang GZ
[Promoting effect of panaxatriol ginsenoside on gene expression of human interleukin-1]
Zhongguo Yao Li Xue Bao. 1993; 14: 159-61
Display abstract
Effect of panaxatriol ginsenoside (PG) on interleukin-1 (IL-1) gene expression was studied by using wheat germ extract (cell-free translation system) and IL-1 bioassay. The results showed that IL-1 production increased by 40% (487-682 U.ml-1) at maximum during cell culture (0-84 h) after PG (10 micrograms.ml-1) was added to phytohemagglutinin (PHA, 50 micrograms.ml-1) stimulated lymph node cells. Meanwhile, IL-1 mRNA from PHA combined with PG stimulated lymph node cells translated 39.5% more IL-1 than that of PHA-stimulated cells at maximum (2500-3489 U/mg RNA).

Leutwyler C, Schalch L, Jungi TW
Evidence for interleukin-1 beta being a necessary but not sufficient co-stimulatory signal in monocyte-dependent anti-CD3-mediated T-cell triggering.
Immunol Lett. 1993; 38: 33-9
Display abstract
T-cell activation by CD3-specific antibodies is either monocyte independent or monocyte mediated, depending on the fine specificity and mode of presentation of anti-CD3. Monocyte-independent activation occurs when T cells encounter surface-bound antibody at high density, thereby mediating interleukin-2 (IL-2) production. Monocyte-dependent activation occurs upon bipolar binding of anti-CD3 to CD3 of T cells and to Fc receptors of accessory cells (monocytes). We addressed the role of interleukin-1 (IL-1) as a co-stimulatory signal in monocyte-dependent anti-CD3-mediated T-cell proliferation by using specific and anti-IL-1 subtype antibodies and IL-1 receptor antagonist (IL-1ra). IL-1ra blocked proliferation of mononuclear cells (MNC) induced by fluid-phase anti-CD3, and proliferation of nylon wool-purified cells (NWPC; < 1% monocytes) exposed to low-density, but not high-density, anti-CD3 coats. Stimulation of MNC by fluid-phase anti-CD3 and of NWPC by low-density anti-CD3 coats could both be blocked by anti-IL-1 beta, but not by anti-IL-1 alpha, although the latter efficiently blocked IL-1 alpha-mediated thymocyte co-stimulation. Neither the addition of IL-1 beta (given alone or combined with IL-6 and/or IL-1 alpha) nor anti-CD3-independent, LPS-induced cytokine induction in monocytes provided the co-stimulatory signal(s) for anti-CD3-triggered T cells in the absence of bipolar anti-CD3 binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Chang ML, Yang LL, Chang DM, Kuo SY, Chu SJ
[The influence of Chinese traditional medicine on the production and activity of interleukin 1 (IL-1)]
Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi. 1993; 26: 15-24
Display abstract
Interleukin 1 (IL-1) is a cytokine closely related to the pathogenesis of inflammation and chronic destructive changes in rheumatoid arthritis (RA). Analysis of the effect of antirheumatic drugs on IL-1 production and activity is of great importance in exploring the therapeutic mechanism of RA. The purpose of the present study was to investigate the effect of Chinese herbs (10 prescription and 15 single drugs), which was often used in the treatment of RA, on the production and activity of IL-1. The production of IL-1 was tested through human monocytes stimulated with zymosan and measured by ELISA method; the activity of IL-1 was measured by its effect on the proliferation of murine thymocytes. The results showed that Tripterygium Wilfordii Hook, Tripterygil Hyhoglauci Tetrandrine significantly inhibited both of IL-1 production and IL-1 activity; while Aconiti Tuber, Ephedrae Herba, Atractyloidis Rhizoma, Atractyloidis Lanceae Rhizoma, Ledebouiellae Radix slightly inhibited IL-1 activity but not affecting IL-1 production. The ten prescriptions had no inhibitory effect on both of IL-1 production and IL-1 activity.

Colotta F et al.
Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4.
Science. 1993; 261: 472-5
Display abstract
Interleukin-1 (IL-1) interacts with cells through two types of binding molecules, IL-1 type I receptor (IL-1R I) and IL-1R II. The function of IL-1R II is unknown. In studies using monoclonal antibodies, IL-1 prolonged the in vitro survival of polymorphonuclear cells (PMN) through IL-1R I, and IL-4 antagonized the action of IL-1 by inducing expression and release of IL-1R II. Dexamethasone also induced expression and release of the IL-1R II in PMN. These results, together with the effect of antibodies to IL-1R on IL-1-induced production of cytokines in monocytes, indicate that IL-1 acts on myelomonocytic cells through IL-1R I and that IL-1R II inhibits IL-1 activity by acting as a decoy target for IL-1. The existence of multiple pathways of regulation emphasizes the need for tight control of IL-1 action.

Dinarello CA
Modalities for reducing interleukin 1 activity in disease.
Trends Pharmacol Sci. 1993; 14: 155-9
Display abstract
The therapeutic advantage of reducing the activity of interleukin 1 (IL-1) resides in preventing its deleterious biological effects without interfering with homeostasis. As such, methods attempting to block the production or activity of IL-1 have now entered clinical trials. For example, IL-1 induction of prostaglandins is one target in treating disease, and drugs preventing the production of inhibiting cyclooxygenase have well-known toxicities because they block the normal synthesis of prostaglandins in many tissues. IL-1 blockading agents, in contrast, affect only that portion of prostaglandin synthesis due to elevated IL-1, sparing the synthesis of these molecules for homeostasis. Charles Dinarello reviews the unique pharmacological advantages of manipulating IL-1.

Tatakis DN
Interleukin-1 and bone metabolism: a review.
J Periodontol. 1993; 64: 416-31
Display abstract
This review discusses the effects of interleukin-1 (IL-1) on bone metabolism and the evidence implicating IL-1 in periodontal disease. IL-1 is a potent cytokine with significant effects on the metabolism of many tissues, including bone. Several in vitro and in vivo studies have established the potent bone-resorbing effect of IL-1. Studies have indicated that IL-1 inhibits bone formation, although it can stimulate formation under certain conditions. Osteoblastic cells are the bone cells expressing IL-1 receptors and responding to IL-1. IL-1 effects on osteoblastic cells include stimulation of prostaglandin formation and modulation of gene expression of several proteins (cytokines, enzymes, enzyme inhibitors, matrix proteins, etc.). Osteoblastic cells also produce IL-1, suggesting an autocrine/paracrine function of IL-1 in bone. IL-1 has been shown to interact with other osteotropic factors, both systemic and local. These interactions modulate the effects of IL-1 on bone. The IL-1 effects on bone metabolism, along with other observations, suggest that IL-1 may be involved in the pathogenesis of bone diseases. Evidence from in vivo and in vitro studies suggests that IL-1 is an important factor in periodontal tissue breakdown. The ability of periodontopathic bacteria to stimulate IL-1 production, the detection of elevated IL-1 levels in periodontally-diseased tissues, and the effects of IL-1 on cells of the periodontium provide a plausible sequence of events in the pathogenesis of periodontal disease. Finally, therapeutic modalities aimed to control the actions of IL-1 are also discussed.

Uehara Y, Shimizu H, Sato N, Mura YS, Mori M
The dipeptide Lys-Pro attenuates interleukin-1 beta-induced anorexia.
Peptides. 1993; 14: 175-8
Display abstract
The carboxyl-terminal tripeptide of alpha-MSH(1-13), Lys-Pro-Val, antagonizes anorexia induced by interleukin-1 beta (IL-1). The present studies were undertaken to determine if the Lys-Pro dipeptide portion of this tripeptide likewise antagonizes anorexia induced by ICV administration of 0.5 pmol IL-1 in rats previously deprived of food. This dose of Lys-Pro did significantly attenuate the IL-1-induced anorexia, but only for 1 h after infusion. Simultaneous administration of a larger dose (5.0 pmol) of Lys-Pro reversed the IL-1-induced anorexia during both the 0-1-h and 2-4-h periods. In addition, both 0.5 and 5.0 pmol of the D-substitute tripeptide, Lys-D-Pro-Thr (LDPT), similarly attenuated the IL-1-induced anorexia. The ICV administration of 5.0 pmol Lys-Pro also did not have any significant effects on food consumption. These results indicate that the dipeptide Lys-Pro may have a short-term antagonistic action against the anorexia induced by IL-1, and it is possible that this action may be partially mediated by the blockade of IL-1 on its own receptor.

Vuotto ML et al.
Inhibition of interleukin-1 release and activity by the rat seminal vesicle protein SV-IV.
J Leukoc Biol. 1993; 53: 214-22
Display abstract
SV-IV, a 9.8-kd protein isolated from rat seminal vesicle secretion, has been shown to have strong non-species-specific immunosuppressive, anti-inflammatory, antithrombotic, and antiphospholipase A2 properties. The present investigation was undertaken to determine the mechanism of action of its immunosuppressive effects. It was found that SV-IV is a potent inhibitor of interleukin-1 (IL-1) release from lipopolysaccharide (LPS)-activated human adherent monocytes and an effective inhibitor of IL-1-induced thymocyte proliferation. The ability of SV-IV to form a noncovalent dimeric association with IL-1 alpha but not with IL-1 beta, its ability to induce a marked decrease of IL-1 binding to its own receptors on the thymocyte surface, and its capacity to bind specifically to the macrophage plasma membrane might play an important role in the molecular mechanism of these inhibitory effects.

Garrett IR, Guise TA, Bonewald LF, Chizzonite R, Mundy GR
Evidence that interleukin-1 mediates its effects on bone resorption via the 80 kilodalton interleukin-1 receptor.
Calcif Tissue Int. 1993; 52: 438-41
Display abstract
Interleukin-1 (IL-1) mediates its effects through two distinct receptors, one of 80 kilodaltons (80 kD) present in athymic lymphocytes and fibroblasts, and one of 60 kD present in cells of the monocyte-macrophage lineage. A novel monocyte cytokine in the IL-1 family which binds to both the 80 and the 60 kD receptors has been purified, cloned, and expressed. As the interleukin-1 receptor antagonist (IL-1ra) has been shown to inhibit bone resorption in organ culture, it is not clear whether these effects are mediated through the 80 or the 60 kD receptor. Recently, neutralizing antibodies (35F5) have been developed to the 80 kD receptor which inhibit IL-1 effects mediated through this receptor. To determine the importance of the 80 kD receptor to IL-1-mediated bone resorption, we used the neutralizing antibodies (35F5) to the 80 kD receptor to determine if they inhibited bone resorption stimulated by IL-1 in bone organ cultures. The 35F5 antibody blocked bone-resorbing activity due to IL-1 completely, and also blocked control or "endogenous" bone-resorbing activity present in murine bone organ cultures incubated in control media. The 35F5 antibody had no effect on bone resorption mediated by tumor necrosis factor (TNF), or parathyroid hormone (PTH). These data suggest that the availability of the 80 kD IL-1 receptor is required for osteoclastic bone resorption mediated by IL-1.

Brody M, Bohm I, Bauer R
Mechanism of action of methotrexate: experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells.
Eur J Clin Chem Clin Biochem. 1993; 31: 667-74
Display abstract
Interleukin 1, a multifunctional cytokine, plays a central role in inflammatory processes and induction of the immune response. Target cells possess 200-5000 (or more) interleukin 1 receptors per cell, but they exhibit a full biological response when only 1-2% of these receptors are occupied by interleukin 1 alpha or 1 beta. Methotrexate has been reported to be beneficial in several inflammatory and autoimmune diseases. On the other hand, many of these diseases are known to share an overproduction of interleukin 1. It has been demonstrated that methotrexate has no influence on the interleukin 1 synthesis, so we focused our attention on the ability of methotrexate to interfere with the binding of interleukin 1 beta to the interleukin 1 receptor. The experiments were performed on monocytes, lymphocytes and granulocytes using a recombinant human cytokine probe. Methotrexate led to an astonishing decrease in the binding of interleukin 1 beta to the interleukin 1 receptor of peripheral blood cells, whereas methylprednisolone and indomethacin were not inhibitory. The inhibitory effect of methotrexate was dose dependent. An excess of interleukin 1 beta abolished the inhibition of cytokine binding by methotrexate. We also demonstrated that methotrexate does not affect the integrity of the interleukin 1 receptor or of the target cells. Our results demonstrate that methotrexate blocks the interleukin 1 beta-interleukin 1 receptor pathway. Methotrexate is therefore another interleukin 1 inhibitor and a clinically efficient anticytokine.

Lederer J, Czuprynski C
Characterization and identification of interleukin-1 receptors on bovine fibroblasts.
Mol Immunol. 1993; 30: 191-6
Display abstract
Interleukin-1 (IL-1), a pro-inflammatory cytokine, initiates its many biological effects by first binding to cell-surface receptors. Prior to this study, there were no published reports addressing the nature of the bovine IL-1 receptor. In this study, we characterized and identified cell-surface IL-1 receptors on bovine fibroblasts. Direct binding studies using [125I]-labeled bovine IL-1 beta demonstrated that bovine fibroblasts had approximately 130 high affinity and 2,500 low affinity binding sites (Kd = 4.9 x 10(-11) M and 3.7 x 10(-9) M, respectively). Competitive binding studies using unlabeled recombinant bovine IL-1 beta, IL-2, IFN-alpha, and bovine insulin demonstrated that only unlabeled bovine IL-1 beta competitively blocked fibroblast binding of [125I]-labeled bovine IL-1 beta. Affinity cross-linking of [125I]-labeled IL-1 beta to fibroblasts demonstrated that IL-1 receptors on bovine fibroblasts have an apparent M(r) of 71.5 kD. This report provides the first characterization and identification of IL-1 receptors on bovine fibroblasts.

Dinarello CA
Blocking interleukin-1 in disease.
Blood Purif. 1993; 11: 118-27
Display abstract
Numerous studies implicate a role for cytokines in the pathogenesis of disease. These are primarily derived from experiments in which cytokines are injected into experimental animals and disease activity is monitored. Other studies measure elevated cytokines in either animals or humans during the development of disease. Although cytokines are thought to play a role in the outcome of various diseases, only a few have been directly implicated as mediators of the pathogenic mechanisms of illness and death of the host. Recent studies using specific cytokine antagonism have shed considerable light on which cytokines appear to be playing a critical role.

Rothwell NJ, Relton JK
Involvement of interleukin-1 and lipocortin-1 in ischaemic brain damage.
Cerebrovasc Brain Metab Rev. 1993; 5: 178-98
Display abstract
The cytokine interleukin-1 (IL-1) is synthesised within the brain and acts as a mediator of host defence responses to disease and injury. Several of these central actions of IL-1 are inhibited by an endogenous calcium and phospholipid binding protein, lipocortin-1. Synthesis of IL-1 and lipocortin-1 in the brain is markedly increased by neuronal damage, and inhibition of the actions of endogenous IL-1 by central injection of IL-1 receptor antagonist in the rat significantly inhibits ischaemic and excitotoxic brain damage. Lipocortin-1 appears to act as an endogenous neuroprotective agent that markedly attenuates ischaemic and excitotoxic damage. In contrast, inhibition of the actions of lipocortin-1 by injection of neutralising antiserum exacerbates both forms of neurodegeneration. The mechanisms underlying these effects of IL-1 and lipocortin-1 are largely unknown, but are probably independent of changes in body temperature. Actions of these molecules on corticotrophin releasing factor, arachidonic acid, excitatory amino acids, and nitric oxide, and the possible involvement of these factors in brain damage are discussed.

Sims JE et al.
Interleukin 1 signaling occurs exclusively via the type I receptor.
Proc Natl Acad Sci U S A. 1993; 90: 6155-9
Display abstract
Two receptors for the proinflammatory cytokine interleukin 1 (IL-1) have been cloned and characterized biochemically. While it has been well established that the type I (80-kDa) IL-1 receptor can mediate responses to IL-1, the function of the type II (60-kDa) IL-1 receptor has been unknown. In this manuscript we describe experiments designed to ask whether the type II receptor is capable of delivering a biological signal. We have examined two types of experimental situation: responses to IL-1 in cells which express predominantly the type II receptor, and responses to IL-1 which have been suggested previously in the literature to be mediated by type II receptors. In both situations we find that the responses instead are mediated via type I receptors. A blocking antibody against the type II receptor never inhibits, and in fact sometimes enhances, the responses. We conclude that a very small number of type I receptors is sufficient to mediate all of the actions of IL-1 which we have examined here and that the function of the type II receptor may not be to transduce signals.

Bureau J, Pouliquen Y, Lorans G
[Fibrocyte reaction to interleukin 1 stimulation in keratoconus. Original title: Fibrocyte response to interleukin 1 stimulation in keratoconus]
Klin Monatsbl Augenheilkd. 1993; 203: 269-74
Display abstract
BACKGROUND: The reduced mechanical strength of the tissues around a keratoconus and the ultrastructural disorganization of its matrix components are caused by proteolytic breakdown and incomplete repair. In most biochemical studies on this subject, reduced collagen content and increased collagenase and gelatinase activity have been reported. METHODS: Since interleukin-1 (IL-1) promotes secretion of prostaglandin E-2 (PG-E2 and collagenase, we were interested in the number of membrane receptors for these cytokines on keratoconus fibroblasts and determined the corresponding dissociation constant (kD). We also studied the kinetics of cyclo-oxygenase and the synthesis of PG-E2, IL-1 and collagen. We compared the data with data from normal human corneas. RESULTS: 1) There was a significant difference (P < 0.05) between the specific binding of [125I]-IL-1 in keratoconic and normal corneal cells. In keratoconus, the number of receptors was four times higher (7000 +/- 100 binding sites per cell) than in normal corneas (1540 +/- 100 binding sites per cell). However, there was little difference between the dissociation constants for keratoconic ([6.21 +/- 0.5] x 10(-11) and normal ([6.27 +/- 0.5] x 10(-11) corneal cells. 2) Under the study conditions, interleukin-1 was found neither in normal nor in keratoconic cornea. 3) Synthesis of PG-E2 without stimulation of cells by IL-1, which was observed in 8 corneas with and 8 without keratoconus, showed that keratoconus cells secrete ten times more PG-E2 than normal corneals cells. If IL-1 is added to the incubation medium, which contains [3H]-labeled arachidonic acid, PG-E2 synthesis increases more than in normal corneal cells. 4) After adding IL-1, the collagen concentration in keratoconus cells in culture was more pronounced than in normal corneal cells. CONCLUSIONS: It is still not known why the anomalies discussed above occur in keratoconus. The increase in IL-1 receptor expression and the high level of cyclooxygenase activity are very probably due to genetic causes, because they are observed even after 40 generations of cell cultures.

Pronost S et al.
Interleukin-1 and naproxen down-regulate the expression of IL-1 receptors in cultured human rheumatoid synovial cells (HRSC).
Agents Actions Suppl. 1993; 39: 213-7
Display abstract
Using affinity binding of [125I]-IL-1 alpha and Scatchard analysis, we demonstrate here that exposure of cultured synovial cells (HRSC) to NPX (10(-4) M) for 96 h decreased the binding of IL-1 by 20 to 35%. This effect results from a down-regulation of the IL-1 receptors without change in the apparent binding affinity (kD: 770 pM). Pretreatment of cultures with IL-1 alpha (500 pg/ml) reduced the total binding of [125I]-IL-1 alpha on HRSC by 65%, indicating that IL-1 decreases the expression of its own receptors.

Otterness IG, Hanson DC, Bliven ML
Possible role of IL-1 in arthritis: effects of prostaglandins in the regulation of IL-1 synthesis and actions.
Agents Actions Suppl. 1993; 39: 109-20

Gayle RB 3rd et al.
Identification of regions in interleukin-1 alpha important for activity.
J Biol Chem. 1993; 268: 22105-11
Display abstract
Saturation mutagenesis of the mature human interleukin-1 alpha (IL-1 alpha) gene has been performed. Following expression in Escherichia coli, the biological and receptor binding activities of the mutant proteins were examined. Most of the molecule could be altered with little effect on either function. More than 3,500 mutants were examined, and only 23 unique amino acid sequences were identified which resulted in an altered ratio of biological to binding activity when compared with wild-type IL-1 alpha. These proteins possessed mutations at 38 of the 159 amino acid residues in IL-1 alpha. Random mutagenesis at several of these positions identified further substitutions that affected activity. Examination of a model for IL-1 alpha localized most of the residues which altered activity along one face of the molecule. This region appears to be distinct from areas of IL-1 which have been postulated to make contact with IL-1 receptor.

Oldfield TJ, Murray-Rust P, Hubbard RE
Model structures and action of interleukin 1 and its antagonist.
Protein Eng. 1993; 6: 865-71
Display abstract
A comparison has been made between the homology and hydrophobicity profiles of six interleukin amino acid sequences and that of the human interleukin 1 beta (IL-1 beta) for which a crystal structure exists. The resulting sequence alignment was used to build model structures for the sequences for three IL-1 alpha, two IL-1 beta and an interleukin receptor antagonist. Analysis of these structures demonstrates that the interleukin molecule has a strong electric dipole which is generated by the topological position of the amino acids in the sequence. Electrostatic surface calculations implicate a particular residues (Lys145) as being fundamental to interleukin activity and this supports site-directed mutation evidence that this residue is required for activity.

Tagliabue A, Boraschi D
Cytokines as vaccine adjuvants: interleukin 1 and its synthetic peptide 163-171.
Vaccine. 1993; 11: 594-5
Display abstract
The possibility of preventing infectious diseases by employing efficacious vaccine is rapidly growing as a consequence of the new technologies in recombinant DNA and protein chemistry. However, the increasing number of synthetic and recombinant antigens further stresses the role of appropriate adjuvants to ensure maximal vaccine activity and the protection of all vaccinees. Several approaches can be applied to develop safe and effective agents capable of enhancing specific immune responses which can then protect the host from the pathogen. Among others, the direct use as adjuvant of those cytokines which are induced in animals by the classical Freund's adjuvants has recently become a matter of investigation. In particular, interleukin 1 (IL-1) has been shown to possess adjuvant activity for a variety of infectious and tumour antigens. However, the numerous side effects associated with the proinflammatory action of IL-1 represent a serious disadvantage for its use as a vaccine adjuvant. It was therefore of great interest that a nonpeptide contained in the IL-1 beta sequence (residues 163-171 corresponding to the sequence VQGEESNDK) is devoid of all proinflammatory activities but maintains the immunostimulating activity of the whole IL-1 beta. Thus, peptide 163-171 was successfully employed in animals to potentiate the specific immune response against T-helper-dependent cellular antigens, T helper-independent polysaccharidic antigens and recombinant as well as synthetic antigenic preparations derived from human pathogens. Furthermore, IL-1 and peptide 163-171 have been successfully used in tumour vaccines in experimental systems. It can therefore be concluded that peptide 163-171 is potentially a good candidate as vaccine adjuvant for human use.

Dinarello CA, Wolff SM
The role of interleukin-1 in disease.
N Engl J Med. 1993; 328: 106-13

Beuscher HU, Rausch UP, Rollinghoff M
[The role of interleukin 1 in infection and sepsis]
Immun Infekt. 1992; 20: 128-33
Display abstract
Interleukin(IL-)-1 is the prototype of a proinflammatory cytokine, produced in response to infection and other forms of trauma. At low concentrations IL-1 brings about increases in a number of defense mechanisms, particularly immunologic and inflammatory responses. However, over- or continued production of IL-1, as seen for example during septic infection, significantly contributes to pathological reactions such as hemodynamic shock. Thus, it is not surprising that IL-1 activities are tightly regulated, most notably at the levels of transcription and secretion. Additional regulation is provided by the action of a protein, that blocks the binding of IL-1 to its receptors. This protein, termed IL-1-receptor antagonist (IL-1ra) has been cloned recently, and may provide the possibility of specific therapeutic measures.

Dinarello CA
The role of interleukin-1 in host responses to infectious diseases.
Infect Agents Dis. 1992; 1: 227-36
Display abstract
The polypeptide cytokine interleukin-1 (IL-1) affects nearly every tissue and organ system. IL-1 is the prototype of the pro-inflammatory cytokines in that it induces the expression of a variety of genes and synthesis of several proteins which, in turn, induce acute and chronic inflammatory changes. Most studies on the biology of IL-1 have been carried out in animals, but human subjects have recently been injected with recombinant IL-1 and the results confirm IL-1 as being a mediator of disease as well as host defense. However, overproduction of IL-1 leads to debilitation of normal host functions; therefore, reduction of IL-1 synthesis or blockade of IL-1 activity becomes a target of therapy in many diseases. Agents for reducing the synthesis or antagonizing the effects of IL-1 have been sought, but the naturally occurring IL-1 receptor antagonist (IL-1Ra) has opened new experimental and clinical approaches. The ability of IL-1Ra to block IL-1 receptors without agonist activities has reduced the severity of diseases such as septic shock, lethal sepsis, inflammatory bowel disease, experimental arthritis, and the spontaneous proliferation of human leukemic cells.

Lachaux A
[Interleukin 1 receptor antagonists]
Pediatrie. 1991; 46: 657-61
Display abstract
Interleukin 1 (IL-1) is a polypeptide cytokine produced by various cell types that mediates a broad range of biological activities and possesses a wide spectrum of immunologic and non immunologic properties. Interest has recently focussed on the role of IL-1 as an inflammatory mediator in chronic and acute diseases. The production of IL-1 inhibitors may be a part of a homeostatic mechanism regulating IL-1 effect on immune and inflammatory cell function. Recent reports concerning the purification, characterization, and expression of a cDNA for an IL-1 receptor antagonist (IL-1ra) have been published. Further study of this protein should be valuable in determining the role of IL-1a in man. The protein should also be useful for studying the list of IL-1 activities. Finally, IL-1a is a potentially useful therapeutic agent for the treatment of IL-1-mediated disease in man.

Feldmann M
Cytokine networks: do we understand them well enough to facilitate clinical benefits?
Eur Cytokine Netw. 1991; 2: 5-9
Display abstract
Cytokines are chiefly local transmitters. The cloning of these molecules has been driven by the belief that they will be of major therapeutic benefit, despite the problems inherent in their clinical administration systemically, a non-physiological route. This brief review discusses the clinical use of cytokines and the possibilities for clinical benefit of interfering with cytokine function. A major step forward in the past few years has been the realization that shed extracellular domains of cytokine receptors are the most common natural cytokine inhibitors, described for TNF, IFN gamma, IL-2, IL-4, IL-7, for example. These natural cytokine inhibitors may offer interesting therapeutic possibilities, as they are enhancing or "replacing" the natural anti-cytokine mechanisms.

Brazel D, Nakanishi S, Oster W
Interleukin-1, characterization of the molecule, functional activity, and clinical implications.
Biotechnol Ther. 1991; 2: 241-67
Display abstract
Hematopoiesis is regulated by a number of growth factors, of which colony-stimulating factors (CSF) have been exclusively defined according to the cell type they grow in vitro in colony assays. A number of cytokines, including interleukin-1 (IL-1), which have been characterized to exhibit multiple activities, are also involved in the control of growth and differentiation of hematopoietic cells. Some CSFs and related cytokines have already been introduced into clinical evaluation. This review summarizes the current knowledge of the IL-1 molecules, their moleculargenetic, and protein features as well as their in vitro and in vivo actions which justify their development as therapeutic agents.

Dinarello CA
Interleukin-1 and interleukin-1 antagonism.
Blood. 1991; 77: 1627-52
Display abstract
The polypeptide cytokine interleukin-1 (IL-1) affects nearly every tissue and organ system. IL-1 is the prototype of the pro-inflammatory cytokines in that it induces the expression of a variety of genes and the synthesis of several proteins that, in turn, induce acute and chronic inflammatory changes. IL-1 is also the prototypic "alarm" cytokine in that it brings about increases in a variety of defense mechanisms, particularly immunologic and hematologic responses. Most studies on the biology of IL-1 have been performed in animals, but human subjects have recently been injected with recombinant IL-1 and the results confirm the two fundamental properties of IL-1 as being both a mediator of disease as well as of host defense. However, in either situation, over or continued production of IL-1 leads to debilitation of normal host functions; therefore, reduction of IL-1 synthesis or its effects becomes a target of therapy in many diseases. In this review, the structure, gene expression, synthesis, and secretion of IL-1 are described. In addition, the two IL-1 surface receptors, possible signal transduction mechanisms, various biologic activities, and production of IL-1 during disease states are discussed. Similarities and differences between IL-1, tumor necrosis factor, and IL-6 are presented. Although various agents for reducing the synthesis and/or for antagonizing the effects of IL-1 have been proposed, the recent cloning of a naturally occurring IL-1 receptor antagonist (IL-1ra) has opened new experimental and clinical approaches. The ability of this IL-1ra to block the triggering of IL-1 receptors in animals without agonist effects has reduced the severity of diseases such as hemodynamic shock, lethal sepsis, inflammatory bowel disease, experimental arthritis, and the spontaneous proliferation of human leukemic cells.

Schaffner H
[Interleukin 1 and hematopoiesis]
Allerg Immunol (Leipz). 1990; 36: 77-86
Display abstract
Interleukin-1 mediates a broad spectrum of activities in the functional network of cytokines. In addition to its function as an inducer of the acute phase response IL-1 has many effects on hemopoiesis in normal and hematologically impaired organisms. This regulatory function is realized by its ability to stimulate the release of hematopoietic growth factors and by its recruiting property for cell cycles of different hemopoietic progenitors and stem cells. IL-1 acts synergistically with the colony-stimulating factors.

Platanias LC, Vogelzang NJ
Interleukin-1: biology, pathophysiology, and clinical prospects.
Am J Med. 1990; 89: 621-9
Display abstract
Interleukin-1 (IL-1) is a cytokine with multiple biologic activities. Since its first description in 1972, significant work has been done, leading to an understanding of the biology of IL-1, which plays a central role in many important functions of the immune system. The biologic activities of IL-1 make it an attractive factor for use in clinical oncology, both as an antitumor agent and for the hematologic recovery of cancer patients receiving other forms of therapy. In this review the biologic effects of IL-1 are summarized. The possible involvement of IL-1 in the pathogenesis of some diseases is reviewed. Future prospects for the use of IL-1 in the treatment of malignancies are discussed.

di Giovine FS, Duff GW
Interleukin 1: the first interleukin.
Immunol Today. 1990; 11: 13-20
Display abstract
The name 'interleukin' and the designation of interleukin 1 (IL-1) derived from the Second International Lymphokine Workshop held in Switzerland in 1979. Since then interest in the original interleukin (IL-1) has increased exponentially as measured by the numbers of publications and meetings. The main reasons for this can be seen in the accompanying centrefold. The perception of IL-1 as a biological mediator in every organ system has attracted scientists from widely different backgrounds into this area and a steady succession of important and often surprising insights into IL-1 biology has ensured that interest has been sustained at a high level. This overview of the biology of IL-1 on the tenth anniversary of its turbulent life has been compiled by Franco di Giovine and Gordon Duff. It is of necessity selective and biased towards human IL-1 and begins with some general points (mainly cautionary) as a backdrop to the centrefold.

Larrick JW
Native interleukin 1 inhibitors.
Immunol Today. 1989; 10: 61-6
Display abstract
Much information has accumulated on the isolation and characterization of a heterogeneous group of molecules that inhibit one or more of the bioactivities of interleukin 1. In this review James Larrick discusses the biological and biochemical data available on several of these native interleukin 1 inhibitors, some of which have additional, unexpected activities.

Dinarello CA, Neta R
An overview on interleukin-1 as a therapeutic agent.
Biotherapy. 1989; 1: 245-54

Yamashita F, Sakakida K, Kusuzaki K, Takeshita H, Kuzuhara A
Immunohistochemical localization of interleukin 1 in human growth cartilage.
Nippon Seikeigeka Gakkai Zasshi. 1989; 63: 562-8
Display abstract
Although it has been reported that interleukin 1 (IL-1) stimulate chondrocytes to produce collagenase and proteoglycanase in vitro, IL-1 producing cells and the function of IL-1 have not been demonstrated in osteocartilaginous tissue in vivo. Immunohistochemical studies of human cartilaginous epiphysis and growth cartilage demonstrated that IL-1 was detected in: (1) chondrocytes surrounding cartilage canal, (2) hypertrophic chondrocytes in cartilaginous epiphysis, (3) chondrocytes at the hypertrophic and calcified zones in the growth cartilage of actively growing bone. In contrast, few hypertrophic chondrocytes showed positive reactions to IL-1 in growth plates nearing physiologic closure. Furthermore, IL-1 was detected in chondrocytes cultured from human growth cartilage. These results show that IL-1 is produced by matured chondrocytes of human growth cartilage in vivo. Chondrocyte-derived IL-1 might play a key role in the hypertrophy of chondrocytes, in the vascularization of cartilage and in the formation of bone.

Nausch M, Friemel H
[Interleukin 1 (IL 1)]
Allerg Immunol (Leipz). 1989; 35: 101-22
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Interleukin 1 is an essential factor of macrophage dependent T cell activation and has a large quantity of other biological activities. This paper gives a review of present knowledge of Interleukin 1. In addition to biochemical properties, the IL 1 production and IL 1 activities, methods for determining of IL 1 and inhibitory factors of IL 1 induced T cell proliferation are described.

Oppenheim JJ, Lew W, Akahoshi T, Matsushima K, Neta R
Aspects of cytokine induced modulation of immunity and inflammation with emphasis on interleukin 1.
Arzneimittelforschung. 1988; 38: 461-5
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Interleukin 1 (IL 1) contributes to both acute and chronic inflammatory processes. Purified IL 1 by itself is only one of the signals that induces local inflammation. The contribution of IL 1 to local inflammatory reactions is influenced by exogenous stimuli, antagonists such as steroid hormones and TGF beta (tissue growth factor beta) and agonists such as TNF (tissue necrosis factor). IL 1 production is depressed by glucocorticoids, but glucocorticoids induce expression of receptors for IL 1 on selected cell types including B lymphocytes and fibroblasts. Thus, complex interactions between hormones and cytokines modulate immunological and inflammatory responses.

Seckinger P, Lowenthal JW, Williamson K, Dayer JM, MacDonald HR
A urine inhibitor of interleukin 1 activity that blocks ligand binding.
J Immunol. 1987; 139: 1546-9
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Urine from febrile patients was found to contain a novel inhibitor of interleukin 1 (IL-1) bioactivity that blocked the specific binding of radioiodinated IL-1 to its receptor in a dose-dependent fashion. Strong inhibition of IL-1 binding was still obtained when cells were preincubated with the inhibitor and washed, thus suggesting that the inhibitor binds to a surface structure (possibly the IL-1 receptor itself). The inhibitor was distinct from IL-1 as determined by both physical parameters (size and antigenicity) and receptor-binding characteristics (apparent affinity and dissociation rate). These data provide evidence for a physiologic regulator of IL-1 activity that functions in vivo via direct interference with ligand binding.

Seckinger P, Dayer JM
Interleukin-1 inhibitors.
Ann Inst Pasteur Immunol. 1987; 138: 486-8

Nasonov EL
[Interleukin 1 and its role in human pathology]
Ter Arkh. 1987; 59: 112-7

Maury CP
Interleukin 1 and the pathogenesis of inflammatory diseases.
Acta Med Scand. 1986; 220: 291-4

Oppenheim JJ, Rossio J, Kimball ES
Properties of human urinary interleukin 1 activities.
Uremia Invest. 1984; 8: 167-73
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A review of the pleiotropic effects and numerous cell sources of interleukin 1 (IL 1) suggests it to be an important intercellular messenger. As such it is of considerable interest that normal human urine contains low molecular weight (4 kd and 2 kd) peptides with the thymocyte comitogenic activity of IL 1. These moieties may represent breakdown products of the usual 15 kd IL 1 peptide. Only the 2 kd but not the 4 kd urinary fraction exhibited the fibroblast proliferation activity of intact IL 1. Furthermore, anion exchange chromatography succeeded in separating the 2 kd fibroblast from the 2 kd thymocyte comitogenic activity. Consequently, determination of the portions of the IL 1 molecule that account for its pleiotropic biological effects will be greatly facilitated. Furthermore, the direct measurement of IL 1 activity in urine of patients with immunologic abnormalities, or with neoplastic or renal disease may prove valuable as a diagnostic and/or prognostic indicator.

Lachman LB
New role for IL-1--muscle protein degradation.
Lymphokine Res. 1983; 2: 109-11

Butler RH, Revoltella RP, Musiani P, Piantelli M
Constitutive production of Interleukin-1 by the human continuous cell line, CM-S.
Cell Immunol. 1983; 78: 368-74
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Supernatants from the human continuous cell line, CM-S, have been tested for Interleukin-1 (IL-1) activity and found to constitutively elaborate this factor. The CM-S-produced IL-1 activity has been partially purified and shown to be similar to IL-1 produced by human and mouse peripheral blood macrophages. To the best of our knowledge this is the first continuous human cell line reported that produces this monokine.