SMART MODE:

NORMAL GENOMIC

• Soussi-Gounni A, Kontolemos M, Hamid Q
• Role of IL-9 in the pathophysiology of allergic diseases.
• J Allergy Clin Immunol. 2001; 107: 575-82
• Display abstract

• Considerable evidence from both human and animal studies indicates that CD4(+) cells are the predominant cell type involved in the regulation of airway inflammation through the expression of T(H)2-type cytokines. The effects of T(H)2-type cytokines, particularly IL-4 and IL-5, on inflammatory and structural cells in airways have been studied in great detail. They were shown to be important for inflammatory cell maturation, activation and proliferation, IgE production, chemokine expression, mucus secretion, and bronchial hyperresponsiveness. Recent work has shown the potential importance of another T(H)2-type cytokine, IL-9. The development of transgenic mice overexpressing IL-9 has suggested a key role for this cytokine in the development of the asthmatic phenotype, including eosinophilic inflammation, bronchial hyperresponsiveness, elevated IgE levels, and increased mucus secretion. IL-9 has been shown to act on many cell types involved in asthma, including T cells, B cells, mast cells, eosinophils, neutrophils, and epithelial cells, and thus might be important in the pathophysiology of allergic asthma.

• Dumoutier L, Louahed J, Renauld JC
• Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9.
• J Immunol. 2000; 164: 1814-9
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• IL-9 is a Th2 cytokine active on various cell types such as T and B lymphocytes, mast cells, and eosinophils, and potentially involved in allergy and asthma. To understand better the molecular mechanisms underlying the activity of this cytokine, we used a cDNA subtraction method to identify genes specifically induced by IL-9 in mouse T cells. One of the IL-9-regulated genes isolated by this approach turned out to encode a 180-amino acid long protein, including a potential signal peptide, and showing 22% amino acid identity with IL-10. This protein, designated IL-10-related T cell-derived inducible factor (IL-TIF), is induced by IL-9 in thymic lymphomas, T cells, and mast cells, and by lectins in freshly isolated splenocytes. Experiments concerning the mechanism regulating IL-TIF expression in T cells indicate that IL-9 induction is rapid (within 1 h), does not require protein synthesis, and depends on the activation of the Janus kinase (JAK)-STAT pathway. In vivo, constitutive expression of IL-TIF was detected by RT-PCR in thymus and brain, suggesting that the role of this new factor is not restricted to the immune system. Transfection of HEK293 cells with the IL-TIF cDNA resulted in the production of a glycosylated protein of about 25 kDa that was found to induce STAT activation in mesangial and neuronal cell lines. Further studies will have to address the possibility that some of the IL-9 activities may be mediated by IL-TIF.

• Chen XJ, Enerback L
• Regulation of IgE-receptor expression, IgE occupancy and secretory capacity of mast cells.
• APMIS. 2000; 108: 633-41
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• Mast cells play an important role in initiating and modulating allergic and inflammatory reactions. Their responsiveness is determined by three important factors: the expression of IgE receptors on the cell surface, the IgE occupancy of these receptors, and the intrinsic secretory capacity of the cells. In this review, we will summarise some findings relevant to these three aspects of mast cell function, and discuss possible regulatory mechanisms. It appears that the genetic background as well as environmental factors influence all three of these components of the response. T cells appear to play an important role in regulating the IgE-receptor expression and also, independently, the intrinsic secretory capacity of mast cells via an unidentified route, possibly involving the secretory signal transduction chain directly. IgE itself appears to have an important role in the regulation of IgE-receptor expression, as indicated by the upregulation of receptors in vitro in the presence of IgE, and the absence of IgE-binding capacity of mast cells in IL-4 gene knockout mice, lacking IgE production. The IgE-receptors of mast cells are saturated to a high degree under different normal conditions, without an obvious relation to antigenic stimulation, also in athymic animals. We have suggested that this basal IgE content on mast cells may be the result of an antigen-independent production of IgE directed by the mast cells themselves and serving regulatory purposes, modifying the secretory response and preventing a massive possibly harmful degranulation.

• Townsend JM, Fallon GP, Matthews JD, Smith P, Jolin EH, McKenzie NA
• IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development.
• Immunity. 2000; 13: 573-83
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• Interleukin-9 is a cytokine produced by Th2 cells and is a candidate gene for asthma and atopy. We have generated IL-9-deficient mice to delineate the specific roles of IL-9 in Th2 responses. Using a pulmonary granuloma model, we have demonstrated a distinct requirement for IL-9 in the rapid and robust generation of pulmonary goblet cell hyperplasia and mastocytosis in response to lung challenge. In contrast, eosinophilia and granuloma formation were not affected. IL-9 was not required for T cell development or differentiation, the generation of naive or antigen-driven antibody responses, or the expulsion of the intestinal parasitic nematode Nippostrongylus brasiliensis. Thus, deletion of IL-9 manifests as a highly defined phenotype in Th2 responses modulating mucus production and mast cell proliferation.

• Hultner L et al.
• In activated mast cells, IL-1 up-regulates the production of several Th2-related cytokines including IL-9.
• J Immunol. 2000; 164: 5556-63
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• Mast cells can play detrimental roles in the pathophysiology and mortality observed in anaphylaxis and other Th2-dominated allergic diseases. In contrast, these cells contribute to protective host defense mechanisms against parasitic worm infections. After IgE/Ag activation, mast cells can produce multiple cytokines that may enhance allergic inflammations, while a similar panel of Th2-related cytokines may support immunological strategies against parasites. Here we report that in primary mouse bone marrow-derived mast cells activated by ionomycin or IgE/Ag, the proinflammatory mediator IL-1 (alpha or beta) up-regulated production of IL-3, IL-5, IL-6, and IL-9 as well as TNF, i.e., cytokines implicated in many inflammatory processes including those associated with allergies and helminthic infections. IL-1 did not induce significant cytokine release in the absence of ionomycin or IgE/Ag, suggesting that Ca-dependent signaling was required. IL-1-mediated enhancement of cytokine expression was confirmed at the mRNA level by Northern blot and/or RT-PCR analysis. Our study reveals a role for IL-1 in the up-regulation of multiple mast cell-derived cytokines. Moreover, we identify mast cells as a novel source of IL-9. These results are of particular importance in the light of recent reports that strongly support a central role of IL-9 in allergic lung inflammation and in host defense against worm infections.

• Perdow-Hickman S, Salgame P
• Rescue of human T cells by interleukin-9 (IL-9) from IL-2 deprivation-induced apoptosis: correlation with alpha subunit expression of the IL-9 receptor.
• J Interferon Cytokine Res. 2000; 20: 603-8
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• Interleukin-9 (IL-9) is a Th2-derived cytokine that uses the gamma-chain of the IL-2 receptor for signaling. Therefore, the responsiveness of human Th1 and Th2 cell clones to IL-9 was measured by examining the ability of this cytokine to prevent apoptosis induced by IL-2 deprivation. A time course study demonstrated that both subsets of T cell clones underwent apoptosis with similar kinetics when deprived of IL-2 and that viability could be maintained by the addition of either IL-4 or IL-7. Interestingly, IL-9 prevented apoptosis in only 2 (Th2) of 14 clones tested. Analysis of IL-9R alpha subunit expression on 18 T cell clones revealed that IL-9 responsiveness was directly proportional to the expression of the high-affinity receptor. IL-9 responsiveness was also dependent on long-term culturing because neither freshly isolated nor 3-day phytohemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBL) expressed IL-9R alpha. In summary, the data showed that IL-9 can rescue only a small subset of Th2 cells from apoptosis induced by growth factor withdrawal and that expression of IL-9R alpha is required for the antiapoptotic signals mediated by this cytokine.

• Stassen M et al.
• Murine bone marrow-derived mast cells as potent producers of IL-9: costimulatory function of IL-10 and kit ligand in the presence of IL-1.
• J Immunol. 2000; 164: 5549-55
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• Recently, the Th2-type cytokine IL-9 was identified by genetic mapping analyses as a key mediator that determines the susceptibility to asthma. This has been further supported by data from IL-9-transgenic mice in which the overexpression of IL-9 in the lung causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. In an accompanying paper, we demonstrate that murine bone marrow-derived mast cells (BMMC) after stimulation with either ionomycin, a combination of ionomycin and IL-1, or via IgE-Ag complexes and IL-1 are very potent producers of IL-9. Herein we show that a dramatic increase of IL-9 production is observed when BMMC activated with ionomycin/IL-1 or with IgE-Ag complexes/IL-1 are treated with either additional kit ligand (KL) or IL-10. Both KL and IL-10 considerably enhance the production of IL-9 mRNA and protein. We were also able to demonstrate that the production of endogenous IL-10 by activated mast cells acts on the production of IL-9. Half-life measurements of IL-9 mRNA revealed no significant effect by KL, but a 2-fold increase of mRNA stability under the influence of IL-10. Reporter gene assays of transfected BMMC showed an enhanced transcriptional activity of the IL-9 promoter in the presence of either IL-10 or KL compared with cells stimulated only with a combination of IL-1 and ionomycin. The influence of KL and IL-10 might be of physiological importance, because it is known that both cytokines are produced by bronchial epithelial cells.

• Love PE, Shores EW
• ITAM multiplicity and thymocyte selection: how low can you go?
• Immunity. 2000; 12: 591-7

• De Smedt M et al.
• Signals from the IL-9 receptor are critical for the early stages of human intrathymic T cell development.
• J Immunol. 2000; 164: 1761-7
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• Highly purified human CD34+ hemopoietic precursor cells differentiate into mature T cells when seeded in vitro in isolated fetal thymic lobes of SCID mice followed by fetal thymus organ culture (FTOC). Here, this chimeric human-mouse FTOC was used to address the role of IL-9 and of the alpha-chain of the IL-9 receptor (IL-9Ralpha) in early human T cell development. We report that addition of the mAb AH9R7, which recognizes and blocks selectively the human high affinity alpha-chain of the IL-9R, results in a profound reduction of the number of human thymocytes. Analysis of lymphoid subpopulations indicates that a highly reduced number of cells undergo maturation from CD34+ precursor cells toward CD4+CD3-CD8-CD1+ progenitor cells and subsequently toward CD4+CD8+ double positive (DP) thymocytes. Addition of IL-9 to the FTOC resulted in an increase in cell number, without disturbing the frequencies of the different subsets. These data suggest that IL-9Ralpha signaling is critical in early T lymphoid development.

• Appasamy PM
• Biological and clinical implications of interleukin-7 and lymphopoiesis.
• Cytokines Cell Mol Ther. 1999; 5: 25-39
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• Interleukin 7 (IL-7) is a stromal cell-derived cytokine that stands out as being the only cytokine identified to date on which development of B and T lymphocytes is absolutely dependent. IL-7 functions primarily as a growth and antiapoptosis factor for B- and T-cell (alphabeta and gammadelta TCR+ cells) precursors, and is essential for differentiation of gammadelta TCR+ cells. IL-7 can function as a cofactor during myelopoiesis, and is capable of activating monocytes/macrophages and natural killer (NK) cells. Its receptor (IL-7R) is a heterodimer of an alpha chain that specifically binds IL-7 and the common gamma chain gammac that is also a component of the receptors for IL-2, IL-4, IL-9 and IL-15. The functions of IL-7 in normal lymphocyte development and activation have led to the demonstration of the ability of IL-7 to stimulate lymphopoiesis in lymphopenic mice, suggesting a possible clinical application of IL-7 in accelerating lymphoid reconstitution in lymphopenic patients. There have also been a number of preclinical studies pointing to the possible utility of IL-7 in antitumor clinical applications, and clinical trials involving IL-7 gene therapy of metastatic disease are underway. IL-7 has also been shown to promote engraftment of stem cells in mice receiving bone marrow transplants, pointing to a possible use of IL-7 in patients receiving bone marrow or peripheral blood stem cell transplants. Areas of IL-7 biology that are essentially unexplored include the mechanisms of regulation of the expression of IL-7 and IL-7Ralpha, as well as the mechanisms by which IL-7 is a growth and differentiation factor for gammadelta T cells but a growth factor only for alphabeta T cells.

• Vink A, Warnier G, Brombacher F, Renauld JC
• Interleukin 9-induced in vivo expansion of the B-1 lymphocyte population.
• J Exp Med. 1999; 189: 1413-23
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• The activity of interleukin (IL)-9 on B cells was analyzed in vivo using transgenic mice that constitutively express this cytokine. These mice show an increase in both baseline and antigen-specific immunoglobulin concentrations for all isotypes tested. Analysis of B cell populations showed a specific expansion of Mac-1(+) B-1 cells in the peritoneal and pleuropericardial cavities, and in the blood of IL-9 transgenic mice. In normal mice, the IL-9 receptor was found to be expressed by CD5(+) as well as CD5(-) B-1 cells, and repeated injections of IL-9 resulted in accumulation of B-1 cells in the peritoneal cavity, as observed in transgenic animals. Unlike other mouse models, such as IL-5 transgenic mice, in which expansion of the B-1 population is associated with high levels of autoantibodies, IL-9 did not stimulate the production of autoantibodies in vivo, and most of the expanded cells were found to belong to the B-1b subset (IgM+Mac-1(+)CD5(-)). In addition, we found that these IL-9-expanded B-1b cells do not share the well-documented antibromelain-treated red blood cell specificity of CD5(+) B-1a cells. The increase of antigen-specific antibody concentration in immunized mice suggests that these B-1 cells are directly or indirectly involved in antibody responses in IL-9 transgenic mice.

• Godfraind C et al.
• Intraepithelial infiltration by mast cells with both connective tissue-type and mucosal-type characteristics in gut, trachea, and kidneys of IL-9 transgenic mice.
• J Immunol. 1998; 160: 3989-96
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• IL-9 transgenic mice were analyzed for the presence of mast cells in different tissues. In these mice, increased mast cell infiltration was found in the gastric and intestinal epithelium as well as in the upper airways and kidney epithelium, but not in other organs, such as skin. IL-9 transgenic mast cells do not show signs of massive degranulation such as that found in IL-4 transgenic mice and are not involved in spontaneous pathologic changes. Gastric mast cells showed a phenotype related to connective-type mast cells, since they were stained by safranin, and strong expression of mouse mast cell protease-4 and -5 was found in this organ. However, they also expressed proteases related to the mucosal cell type, such as mouse mast cell protease-1 and -2. In vitro, although IL-9 by itself did not induce mast cell development from bone marrow progenitors, it strongly synergized with stem cell factor for the growth and differentiation of mast cells expressing the same protease pattern as that observed in IL-9 transgenic mice. Since constitutive stem cell factor expression was observed in vivo, and anti-c-Kit Abs inhibited IL-9 transgenic mastocytosis in the gut, this synergistic combination of factors is likely to be responsible for the mastocytosis observed in IL-9 transgenic mice. Taken together, these data demonstrate that IL-9 induces the in vivo amplification of a nonclassical mast cell subset with a mucosal localization but expressing proteases characteristic of both connective tissue-type and mucosal mast cells.

• Grasso L et al.
• Molecular analysis of human interleukin-9 receptor transcripts in peripheral blood mononuclear cells. Identification of a splice variant encoding for a nonfunctional cell surface receptor.
• J Biol Chem. 1998; 273: 24016-24
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• Genetic studies on mouse models of asthma have identified interleukin-9 (IL9) as a determining factor in controlling bronchial hyperresponsiveness, a hallmark of the disease. Recently, the human IL9 receptor (hIL9R) gene locus has also been implicated in determining susceptibility to bronchial hyperresponsiveness and asthma. In order to evaluate the structure and function of the encoded product, we analyzed receptor transcripts derived from peripheral blood mononuclear cells of 50 unrelated donors. Sequence analysis of the entire coding region identified a splice variant that contains an in frame deletion of a single residue at codon 173 (DeltaQ). This variant could be permanently expressed in a cytokine-dependent murine T-cell line but lacked the ability to induce proliferation in response to human IL9. In situ analyses of cells expressing the wild-type and DeltaQ receptors found both forms to be expressed at the cell surface, but the DeltaQ receptor was unable to bind hIL9 and could not be recognized by N-terminal specific antibodies. These findings demonstrate that hIL9RDeltaQ presents an altered structure and function and suggests its potential role in down-regulating IL9 signaling in effector cells and associated biological processes.

• Keegan AD, Zamorano J
• Regulation of gene expression, growth, and cell survival by IL-4: contribution of multiple signaling pathways.
• Cell Res. 1998; 8: 1-13
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• Interleukin-4 is a cytokine produced by activated T cells, mast cells, and basophils that elicits many important biological responses[1] (see Tab 1). These responses range from the regulation of helper T cell differentiation[2] and the production of IgE[3] to the regulation of the adhesive properties of endothelial cells via VCAM-1[4]. In keeping with these diverse biological effects, high-affinity binding sites for IL-4 (Kd 20 to 300 pM) have been detected on many hematopoietic and non-hematopoietic cell types at levels ranging from 50 to 5000 sites per cell[5]. This review will focus on the discrete signal transduction pathways activated by the IL-4 receptor and the coordination of these individual pathways in the regulation of a final biological outcome.

• Temann UA, Geba GP, Rankin JA, Flavell RA
• Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness.
• J Exp Med. 1998; 188: 1307-20
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• Interleukin (IL)-9, a pleiotropic cytokine produced by the Th2 subset of T lymphocytes has been proposed as product of a candidate gene responsible for asthma. Its wide range of biological functions on many cell types involved in the allergic immune response suggests a potentially important role in the complex pathogenesis of asthma. To investigate the contributions of IL-9 to airway inflammation and airway hyperresponsiveness in vivo, we created transgenic mice in which expression of the murine IL-9 cDNA was regulated by the rat Clara cell 10 protein promoter. Lung selective expression of IL-9 caused massive airway inflammation with eosinophils and lymphocytes as predominant infiltrating cell types. A striking finding was the presence of increased numbers of mast cells within the airway epithelium of IL-9-expressing mice. Other impressive pathologic changes in the airways were epithelial cell hypertrophy associated with accumulation of mucus-like material within nonciliated cells and increased subepithelial deposition of collagen. Physiologic evaluation of IL-9-expressing mice demonstrated normal baseline airway resistance and markedly increased airway hyperresponsiveness to inhaled methacholine. These findings strongly support an important role for IL-9 in the pathogenesis of asthma.

• Robbens J et al.
• Murine adseverin (D5), a novel member of the gelsolin family, and murine adseverin are induced by interleukin-9 in T-helper lymphocytes.
• Mol Cell Biol. 1998; 18: 4589-96
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• We identified a number of upregulated genes by differential screening of interleukin-9-stimulated T-helper lymphocytes. Interestingly, two of these messengers encode proteins that are similar to proteins of the gelsolin family. The first displays a typical structure of six homologous domains and shows a high level of identity (90%) with bovine adseverin (or scinderin) and may therefore be considered the murine adseverin homolog. The second encodes a protein with only five segments. Sequence comparison shows that most of the fifth segment and a short amino-terminal part of the sixth segment (amino acids 528 to 628 of adseverin) are missing, and thus, this form may represent an alternatively spliced product derived from the same gene. The corresponding protein is called mouse adseverin (D5). We expressed both proteins in Escherichia coli and show that mouse adseverin displays the typical characteristics of all members of the gelsolin family with respect to actin binding (capping, severing, and nucleation) and its regulation by Ca2+. In contrast, mouse adseverin (D5) fails to nucleate actin polymerization, although like mouse adseverin and gelsolin, it severs and caps actin filaments in a Ca2+-dependent manner. Adseverin is present in all of the tissues and most of the cell lines tested, although at low concentrations. Mouse adseverin (D5) was found only in blood cells and in cell lines derived from T-helper lymphocytes and mast cells, where it is weakly expressed. In a gel filtration experiment, we demonstrated that mouse adseverin forms a 1:2 complex with G actin which is stable only in the presence of Ca2+, while no stable complex was observed for mouse adseverin (D5).

• Cosman D, Kumaki S, Anderson D, Kennedy M, Eisenman J, Park L
• Interleukin 15.
• Biochem Soc Trans. 1997; 25: 371-4

• Boesteanu A, Silva AD, Nakajima H, Leonard WJ, Peschon JJ, Joyce S
• Distinct roles for signals relayed through the common cytokine receptor gamma chain and interleukin 7 receptor alpha chain in natural T cell development.
• J Exp Med. 1997; 186: 331-6
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• The commitment, differentiation, and expansion of mainstream alpha/beta T cells during ontogeny depend on the highly controlled interplay of signals relayed by cytokines through their receptors on progenitor cells. The role of cytokines in the development of natural killer (NK)1(+) natural T cells is less clearly understood. In an approach to define the role of cytokines in the commitment, differentiation, and expansion of NK1(+) T cells, their development was studied in common cytokine receptor gamma chain (gammac) and interleukin (IL)-7 receptor alpha (IL-7Ralpha)-deficient mice. These mutations block mainstream alpha/beta T cell ontogeny at an early prethymocyte stage. Natural T cells do not develop in gammac-deficient mice; they are absent in the thymus and peripheral lymphoid organs such as the liver and the spleen. In contrast, NK1(+) T cells develop in IL-7Ralpha-deficient mice in the thymus, and they are present in the liver and in the spleen. However, the absolute number of NK1(+) T cells in the thymus of IL-7Ralpha-deficient mice is reduced to approximately 10%, compared to natural T cell number in the wild-type thymus. Additional data revealed that NK1(+) T cell ontogeny is not impaired in IL-2- or IL-4-deficient mice, suggesting that neither IL-2, IL-4, nor IL-7 are required for their development. From these data, we conclude that commitment and/or differentiation to the NK1(+) natural T cell lineage requires signal transduction through the gammac, and once committed, their expansion requires signals relayed through the IL-7Ralpha.

• Faulkner H, Humphreys N, Renauld JC, Van Snick J, Grencis R
• Interleukin-9 is involved in host protective immunity to intestinal nematode infection.
• Eur J Immunol. 1997; 27: 2536-40
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• Murine studies have demonstrated that, as with other nematodes, infection with the intestinal nematode Trichinella spiralis is associated with a pronounced intestinal mastocytosis, eosinophilia and an elevation in serum levels of total IgE. Both interleukin (IL)-4 and IL-5 are clearly important in the generation of IgE responses and eosinophilia, respectively, but the control of mucosal mastocytosis in vivo is not as well defined. Mucosal mast cells appear to be particularly important with regard to T. spiralis infections as there is good evidence to suggest their involvement in expulsion of the parasite from the host. In this study we examined the effect of the overproduction of the Th2 cytokine IL-9 on infection with this nematode. We demonstrate that naive IL-9-transgenic mice have an intense intestinal mastocytosis and high serum levels of mouse mast cell protease-1. Moreover, upon infection high titers of parasite-specific IgG1 were observed with a heightened mast cell response, which was associated with the rapid expulsion of T. spiralis from the gut. Furthermore, as depression of this mast cell response, using anti-c-kit antibodies, resulted in the inability of these mice to expel the parasite, this study clearly demonstrates an activity of IL-9 on mucosal mastocytosis and the host protective immune response in vivo.

• Seymour JF, Kurzrock R
• Interleukin-6: biologic properties and role in lymphoproliferative disorders.
• Cancer Treat Res. 1996; 84: 167-206

• Nechushtan H, Razin E
• Regulation of mast cell growth and proliferation.
• Crit Rev Oncol Hematol. 1996; 23: 131-50

• Lindemann A, Mertelsmann R
• Interleukin-3 and its receptor.
• Cancer Treat Res. 1995; 80: 107-42

• Rubin JT
• Interleukin-2: its rationale and role in the treatment of patients with cancer.
• Cancer Treat Res. 1995; 80: 83-105

• Du X, Williams DA
• Update on development of interleukin-11.
• Curr Opin Hematol. 1995; 2: 182-8
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• This paper reviews the recent studies of interleukin-11 gene expression and regulation, receptor and signal transduction, pharmacologic effects, and preclinical and clinical studies. Interleukin-11 is expressed in cells of mesenchymal origin and gene expression can be modulated by several inflammatory cytokines and agonists. The signaling pathways involved in cytokine induction of interleukin-11 gene expression vary between cell types. In vitro and in vivo studies reveal that interleukin-11 displays a wide spectrum of bioactivities including responses in hematopoietic and nonhematopoietic cells. Preclinical studies in animal models suggest that interleukin-11 may be useful in acceleration of the recoveries of both hematopoietic cells and gastrointestinal mucosal cells after cytoablative therapies. Several clinical studies have demonstrated interleukin-11 to be well tolerated and suggest interleukin-11 is a promising cytokine to prevent both neutropenia and thrombocytopenia in patients with cancer who are receiving chemotherapy.

• Renauld JC, Kermouni A, Vink A, Louahed J, Van Snick J
• Interleukin-9 and its receptor: involvement in mast cell differentiation and T cell oncogenesis.
• J Leukoc Biol. 1995; 57: 353-60
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• Interleukin-9 (IL-9) is a multifunctional cytokine produced by activated TH2 clones in vitro and during TH2-like T cell responses in vivo. The IL-9 receptor is a member of the hemopoietin receptor superfamily and interacts with the gamma chain of the IL-2 receptor for signal transduction. Various observations indicate that IL-9 is actively involved in mast cell responses by inducing the proliferation and differentiation of these cells. The role of IL-9 in T cell responses is less clear. Although freshly isolated normal T cells do not respond to IL-9, this cytokine induces the proliferation of murine T cell lymphomas in vitro and in vivo overexpression of IL-9 results in the development of thymic lymphomas. In the human, the existence of an IL-9-mediated autocrine loop has been suggested for some malignancies such as Hodgkin's disease. Other potential biological targets for IL-9 include B lymphocytes, hematopoietic progenitors, and immature neuronal cell lines.

• Fujiwara H, Hamaoka T
• [Antineoplastic effects of interleukin-12]
• Nihon Rinsho Meneki Gakkai Kaishi. 1995; 18: 611-5

• Appasamy PM
• Interleukin-7 and lymphopoiesis: biological and clinical implications.
• Cancer Treat Res. 1995; 80: 235-60

• Louahed J, Kermouni A, Van Snick J, Renauld JC
• IL-9 induces expression of granzymes and high-affinity IgE receptor in murine T helper clones.
• J Immunol. 1995; 154: 5061-70
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• Interleukin 9 (IL-9) is a TH2 cytokine that has been shown to promote the antigen-independent growth of some mouse T helper clones. To characterize the specificity of IL-9-mediated T cell activation, we used a murine T cell clone that could grow with either IL-9 or IL-2. After differential hybridization of a cDNA library, we isolated three genes that were expressed preferentially in the presence of IL-9. Two of them correspond respectively to granzyme A and granzyme B, two proteases expressed by activated T cells. By Northern blot hybridization and functional assays, we found that IL-9 induced the expression of granzyme B in several T cell clones as well as in mast cell lines. In addition, other proteases such as the mouse mast cell proteases were also found to be expressed by IL-9-activated T cell clones. The third IL-9-induced cDNA corresponds to the alpha-chain of the high-affinity receptor for IgE. Several T cell clones expressed this IgE receptor mRNA and were able to bind IgE with high affinity. Taken together, our results indicate that IL-9 induces a mast cell-like phenotype in T cell clones.

• Takatsu K
• Interleukin-5: an overview.
• Cancer Treat Res. 1995; 80: 187-208

• Puri RK
• Structure and function of interleukin-4 and its receptor.
• Cancer Treat Res. 1995; 80: 143-85

• Houssiau FA et al.
• Human T cell lines and clones respond to IL-9.
• J Immunol. 1993; 150: 2634-40
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• The activity of IL-9 on human T cells was investigated. Human T cell lines and clones, derived from PBMC by stimulation with PHA, IL-2, and irradiated allogeneic PBMC, were found to express a strong IL-9R message at the RNA level and to proliferate in the presence of IL-9, irrespectively of their CD4+ or CD8+ phenotype. Moreover, tumor-specific CTL clones also responded to IL-9. Contrasting with other T cell growth factors, such as IL-2, IL-4, or IL-7, IL-9 did not induce the proliferation of freshly isolated T cells. However, a significant proliferative response to IL-9 could be observed after a 10-day activation of PBMC with PHA, IL-2, and feeders. Taken together, our results indicate 1) that the activity of IL-9 on human T cells is wider than initially anticipated on the basis of the data obtained so far with murine cells; and 2) that proliferative responses to IL-9 require previous activation.

• Lindemann A, Mertelsmann R
• Interleukin-3: structure and function.
• Cancer Invest. 1993; 11: 609-23

• Mahanty S, Nutman TB
• The biology of interleukin-5 and its receptor.
• Cancer Invest. 1993; 11: 624-34
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• IL-5 is primarily a T-cell-derived cytokine that has multiple regulatory functions on eosinophils and (in the mouse) on antibody-secreting B cells. A complex network of cytokines appear to control transcription of the gene for IL-5 and its production. Abnormally high levels of this cytokine are associated with infections with tissue-dwelling parasites and a diverse group of hypereosinophilic conditions of no known etiology. Our understanding of the biological role of IL-5 in the regulation of Ig production and the development of immunity to parasites is far from complete, but basic knowledge of its action at the cellular level is accumulating and will be critical for the intelligent application of immunotherapy with IL-5 or antibodies to IL-5 in infectious, neoplastic, and possibly other diseases.

• Renauld JC, Houssiau F, Uyttenhove C, Vink A, Van Snick J
• Interleukin-9: a T-cell growth factor with a potential oncogenic activity.
• Cancer Invest. 1993; 11: 635-40

• Vink A, Renauld JC, Warnier G, Van Snick J
• Interleukin-9 stimulates in vitro growth of mouse thymic lymphomas.
• Eur J Immunol. 1993; 23: 1134-8
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• The ability of interleukin (IL)-9 to stimulate the in vitro proliferation of freshly collected mouse thymic lymphoma cells was tested on a panel of 45 tumors, induced by N-methyl-N-nitrosourea (MNU) or by X-ray irradiation. IL-9 significantly stimulated the proliferation of 26 of these tumors. Out of 11 other factors tested, only IL-2, IL-4 and IL-7 showed similar activities. In addition to the responses to IL-9 alone, a potent synergy was often observed between IL-9 and IL-2 for MNU-induced tumors. Synergies between IL-9 and IL-7 or IL-9 and IL-4 were also observed but less frequently. The growth-promoting activity of IL-9 and the synergistic activities of IL-2 and IL-9 for thymic lymphoma cells were confirmed with cell lines established from the fresh tumors.

• Costello R, Imbert J, Olive D
• Interleukin-7, a major T-lymphocyte cytokine.
• Eur Cytokine Netw. 1993; 4: 253-62
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• IL-7 is a single-chain 25 kDa protein first identified in bone marrow cultures through its pre-B cell growth factor properties, then also described as a potent T-lymphocyte growth factor. This review relates to the molecular and functional aspects of interleukin-7 (IL-7) and its receptor (IL-7R). We focused on the role of IL-7 in T-cell activation, cytotoxicity generation, leukemic cell growth and immunotherapy.

• Sonoda Y
• [Function, molecular structure and gene expression regulation of interleukin 9 (IL-9)]
• Nippon Rinsho. 1992; 50: 1821-6
• Display abstract

• Interleukin-9 (IL-9)/P40 is a recently reported murine growth factor for helper T-cell clones. It is produced by ConA stimulated CD4+ T-cells or several T-cell lines such as TUC 2.15 derived from C57Bl/6 mouse. In the murine system, IL-9/P40 directly supported proliferation of mucosal type mast cells, and also induced erythroid burst formation, indirectly. On the other hand, human IL-9, which is a homologue to murine P40, was cloned from a cDNA library prepared with mRNA isolated from PHA-induced T-cell line (C5MJ2). Analysis of the sequence of cDNA revealed a striking similarity between murine and human IL-9/P40. Human IL-9 supported formation of a subpopulation of erythroid bursts that are responsive to IL-3. In this communication, identification, cloning of cDNA, and biological activities of murine and human IL-9/P40 are discussed.

• Yang YC
• Human interleukin-9: a new cytokine in hematopoiesis.
• Leuk Lymphoma. 1992; 8: 441-7
• Display abstract

• IL-9 was first identified in the mouse system as a T cell growth factor while human IL-9 was isolated based on its activity on a human myeloid leukemic cell line. The high sequence homology between mouse and human IL-9 plus the preliminary biological analysis have predicted a wide spectrum of in vitro biological activities for this cytokine. Despite the high sequence homology between mouse and human IL-9, many biological activities, however, have not been demonstrated in both species. In vivo studies therefore become essential to understand the physiological role of IL-9. Increasing evidence have also suggested the possible role of IL-9 in the pathogenesis of HD and LCAL. Detailed analysis of IL-9 expression, autocrine growth and clinical outcome of HD patients will be required to make any speculation on the role of this cytokine in the disease states.

• Paukovits WR, Guigon M, Najman A
• Inhibitors of hematopoiesis. Report on the 2nd International Conference on Negative Regulators of Hematopoiesis, Providence, R.I., 22-25 August 1990.
• J Cancer Res Clin Oncol. 1991; 117: 79-84

• Ihle JN
• The molecular and cellular biology of interleukin-3.
• Year Immunol. 1989; 5: 59-102

• Koyasu S
• [Cytokines and receptors--their functions, structures and cloning of code genes. Interleukin-3]
• Nippon Rinsho. 1988; 46: 1008-13

• Paul NL, Ruddle NH
• Lymphotoxin.
• Annu Rev Immunol. 1988; 6: 407-38
• Display abstract

• LT was one of the first lymphokines to be described and has been one of the most difficult to fit into a conceptual framework. Now, 20 years after its discovery, its structure, genetic organization, and linkage are well understood in mouse and human, and insight has been gained into its biological role. It is a T cell-derived glycoprotein of 25 kd coded by a gene within the MHC. It is somewhat (35%) structurally homologous to the macrophage product TNF. The genes for LT and TNF are tightly linked, and the proteins share most biological activities and compete for the same cell surface receptor. LT is induced in an antigen-specific MHC restricted fashion from class I and class II restricted T cells. Viral infection is also associated with LT production by lymphoid cells. LT has several effects on target cells including killing, growth stimulation, and induction of differentiation. The mechanism of LT's effects involves receptor binding and internalization and several sequelae including changes in prostaglandins and chromosome integrity. LT probably plays several biological roles. It can contribute to immunoregulation, defense against viruses, parasitic infections, and rejection of tumors. Understanding LT's role in the pathogenesis of diseases of autoimmunity and immune dysregulation will be the key to devising effective regimens for prophylaxis and treatment.

• Ihle JN
• Biochemical and biological properties of interleukin-3: a lymphokine mediating the differentiation of a lineage of cells that includes prothymocytes and mastlike cells.
• Contemp Top Mol Immunol. 1985; 10: 93-119

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