SMART MODE:

NORMAL GENOMIC

• Matsushima K
• Chemokines. Introduction.
• Springer Semin Immunopathol. 2000; 22: 321-8

• Wang W et al.
• Identification of a novel chemokine (CCL28), which binds CCR10 (GPR2).
• J Biol Chem. 2000; 275: 22313-23
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• We report the identification and characterization of a novel CC chemokine designated CCL28 and its receptor CCR10, known previously as orphan G-protein-coupled receptor GPR2. Human and mouse CCL28 share 83% identity at the amino acid and 76% at the nucleic acid levels. We also identified the mouse homologues of CCL28 and of CCR10, which map to mouse chromosomes 13 and 11, respectively. CCL28 is expressed in a variety of human and mouse tissues, and it appears to be predominantly produced by epithelial cells. Both human and mouse CCL28 induce calcium mobilization in human and mouse CCR10-expressing transfectants. CCL28 desensitized the calcium mobilization induced in CCR10 transfectants by CCL27, indicating that these chemokines share this new chemokine receptor. In vitro, recombinant human CCL28 displays chemotactic activity for resting CD4 or CD8 T cells.

• Shields DC
• Gene conversion among chemokine receptors.
• Gene. 2000; 246: 239-45
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• It has been proposed that proteins which are involved in host defence and susceptibility undergo accelerated evolution. Chemokine receptors have roles as pro-inflammatory agents acting in response to infection, and in addition are receptors for entry of viruses and other pathogens into cells. Consistent with this, their rate of evolution is higher than that for other members of the seven-transmembrane domain receptor family. The pattern of evolution of the chemokine receptors was examined in detail. Both chromosomal clusters of chemokine receptors (CC and CXC) showed evidence of a number of gene conversions. These are likely to have resulted in protein sequence changes, which could possibly alter function. 45% of a control group of clustered genes also showed evidence of conversion. Thus, the fixation of a gene conversion is not in itself sufficiently unusual in tandemly repeated genes and cannot be taken as strong evidence of a selection for a novel function. However, the degree of amino acid difference between the chemokine receptors CCR1 and CCR3 was greater than that for any of the control genes. Such changes could have functional implications for inter-species differences in chemokine receptor interactions with pathogens.

• Baird JW et al.
• ESkine, a novel beta-chemokine, is differentially spliced to produce secretable and nuclear targeted isoforms.
• J Biol Chem. 1999; 274: 33496-503
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• Using the murine embryonal stem cell system, we have identified a novel gene encoding a highly divergent member of the beta-chemokine family of proinflammatory mediators and have called this protein ESkine. Much of the coding sequence for ESkine overlaps with the 3'-end of a novel interleukin 11 receptor alpha-like sequence on murine chromosome 4. ESkine is produced as two splice variants. One of these variants encodes a classical chemokine with an associated signal peptide, while the other variant (PESKY) possesses the main body of the chemokine but has replaced the signal peptide with an alternative stretch of amino acids that allows for nuclear targeting of this isoform. This differential splicing arises as a result of alternative 5' exon usage. These differentially spliced forms are expressed at discrete tissue loci. Thus, while ESkine is highly expressed in the placenta, PESKY is mainly expressed in the Testes and brain and weakly in the developing embryo. Studies on the proinflammatory properties of ESkine reveal it to be active in inducing polarization of CD4(+) T cells but to be inactive on other hemopoietic cellular populations.

• Zlotnik A, Morales J, Hedrick JA
• Recent advances in chemokines and chemokine receptors.
• Crit Rev Immunol. 1999; 19: 1-47
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• Chemokines are a superfamily of small cytokine-like molecules which have been described primarily on the basis of their ability to mediate the migration of verious cell types, particularly those of lymphoid origin. The receptors for these molecules are all seven-transmembrane domain G protein-coupled receptors that have historically been excellent targets for small-molecule drugs. This fact, coupled with the advent of large-scale DNA database mining and the recognition that chemokine receptors are also coreceptors for HIV, has driven discovery in this field at a tremendous rate. This process has included not just an expansion of the number of known chemokines and chemokine receptors, but also a greater appreciation for the variety of functions that chemokines are involved in. We review here the molecules that have come from the most recent years of chemokine research as well as many of the new functions that have been ascribed to them.

• Van Coillie E, Van Damme J, Opdenakker G
• The MCP/eotaxin subfamily of CC chemokines.
• Cytokine Growth Factor Rev. 1999; 10: 61-86
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• Migration of leukocytes from the bone marrow to the circulation, the primary lymphoid organs and inflammatory sites is directed by chemokines and specific receptor interactions. Besides the role of this group of low molecular weight cytokines in leukocyte attraction and activation, anti-HIV and hematopoietic activities were also attributed to chemokines. On the basis of the number and arrangement of the conserved cysteines, chemokines are subdivided in two multi-member families, namely the CXC and CC chemokines, whereas fractalkine (CX3C) and lymphotactin (C) are unique relatives. The CC chemokines possess four cysteines of which the first two are adjacent. Functionally, they form a rather heterogeneous family. Here, the focus is on the monocyte chemotactic proteins and eotaxin which, on a structural basis, can be considered as a CC chemokine subfamily. Not only the protein sequences, but also the gene structures, chromosomal location, biological activities and receptor usage exhibit considerable similarities. The review is complemented with a comparison of the biological functions of the MCP/eotaxin-subfamily in physiology and pathology.

• Rajarathnam K, Crump MP, Clark-Lewis I, Sykes BD
• Spectroscopic characterization of chemokines: relevance for quality control and standardization.
• Dev Biol Stand. 1999; 97: 49-57
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• Chemokines are mediators of inflammation and trafficking of cells of the immune system including a pivotal role in the recruitment and activation of leukocytes. Due to their involvement in a variety of disease processes, chemokines are potential therapeutic targets. The use of chemokines as pharmaceuticals will require that the folded state and the association properties of the protein are well characterized. In this report, we describe the utility of nuclear magnetic resonance spectroscopy as a tool to study these aspects of chemokine structural properties.

• Gupta SK, Pillarisetti K, Gray SL, Stadel JM
• Molecular cloning of a novel chemokine receptor-like gene from early stage chick embryos.
• Biochem Mol Biol Int. 1998; 44: 673-81
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• Proliferation, differentiation and regulated trafficking of cells are the hallmarks of development and embryogenesis. This led us to speculate a role for chemokines and their receptors in this process. Here, we report the molecular cloning of AvCRL1, a novel member of the G-protein coupled receptor family from early stage 3 days old chick embryos. While the function and ligand for this receptor remain unknown, its sequence and gene structure indicates that it is most related to the family of chemokine receptors, with highest homology to the virally induced human BLR-1 and the CXCR3 or gammaIP-10/Mig-1 receptors.

• Mukaida N, Harada A, Matsushima K
• Interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF/MCP-1), chemokines essentially involved in inflammatory and immune reactions.
• Cytokine Growth Factor Rev. 1998; 9: 9-23
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• Leukocyte infiltration is a hallmark of inflammation. Knowledge on molecular mechanisms of leukocyte infiltration has advanced rapidly due to the recent elucidation of structures and functions of adhesion molecules and chemokines. Since the discovery of interleukin-8 (IL-8), a prototype of CXC chemokines, in 1987 and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 (MCAF/MCP-1), a prototype of chemotactic cytokines (CC) chemokines, in 1989, more than 30 members of chemokines have been identified so far. Evidence is accumulating that these chemokines exert overlapping but distinct actions on specific types of leukocytes in vitro through interacting with their specific G-protein-coupled receptors with seven transmembrane domains. However, redundancy at receptor levels has frequently hindered the clarification on the precise physiological or pathophysiological roles of chemokines. Here, we describe the pathophysiological roles of IL-8 and MCAF/MCP-1 in several animal models of neutrophil- and macrophage-mediated inflammation, respectively, by focusing on our recent work using neutralizing antibodies to these chemokines. We discuss further potential roles of these chemokines in T-lymphocyte-mediated immune responses.

• Nomiyama H
• [Novel chemokines identified through bioinformatics]
• Seikagaku. 1998; 70: 558-61

• Murphy PM
• Neutrophil receptors for interleukin-8 and related CXC chemokines.
• Semin Hematol. 1997; 34: 311-8
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• Both the beneficial and harmful roles of neutrophils are critically dependent on the capacity of the cell to undergo directed migration from the blood to local tissue sites. Because the CXC chemokine interleukin-8 (IL-8) is a powerful mediator of this process, its receptor is a reasonable target for development of treatments for neutrophil-mediated inflammation. However, this strategy has been complicated by the discovery of two distinct IL-8 receptors, CXCR1 and CXCR2, that are coexpressed on human neutrophils. Both are 7-transmembrane domain-type proteins functionally coupled to G proteins. Although both receptors bind IL-8 with high affinity, they differ in selectivity for other CXC chemokines, as well as in their regulation and signal transduction, but whether they also differ biologically is not yet clear.

• Hromas R et al.
• Isolation and characterization of Exodus-2, a novel C-C chemokine with a unique 37-amino acid carboxyl-terminal extension.
• J Immunol. 1997; 159: 2554-8
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• Chemokines are a group of small, homologous proteins that regulate leukocyte migration, hemopoiesis, and HIV-1 absorption. We report here the cloning and characterization of a novel murine and human C-C chemokine termed Exodus-2 for its similarity to Exodus-1/MIP-3alpha/LARC, and its chemotactic ability. This novel chemokine has a unique 36 or 37 (murine and human, respectively) amino acid carboxyl-terminal extension not seen in any other chemokine family member. Purified recombinant Exodus-2 was found to have two activities classically associated with chemokines: inhibiting hemopoiesis and stimulating chemotaxis. However, Exodus-2 also had unusual characteristics for C-C chemokines. It selectively stimulated the chemotaxis of T-lymphocytes and was preferentially expressed in lymph node tissue. The combination of these characteristics may be a functional correlate for the unique carboxyl-terminal structure of Exodus-2.

• Wells TN, Schwartz TW
• Plagiarism of the host immune system: lessons about chemokine immunology from viruses.
• Curr Opin Biotechnol. 1997; 8: 741-8
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• In their attempts to evade the host immune response, mammalian viruses have evolved a wide range of strategies. These include the expression and modification of various host cytokines and receptors. Understanding the mechanism of action of these virally encoded proteins will clearly deepen our insights into immunology. In the past few months several new virally encoded chemokines have been described which can modify both the host immune and antiviral response. Their manipulation of the cytokine structure-function relationship may also be useful in the development of reagents for treating immune and proliferative diseases.

• Farber JM
• Mig and IP-10: CXC chemokines that target lymphocytes.
• J Leukoc Biol. 1997; 61: 246-57
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• Mig and IP-10 are related members of the CXC subfamily of the chemokine family of cytokines. The murine Mig (MuMig), human IP-10, and the mouse homologue of IP-10, Crg-2, were all identified due to the dramatic inductions of their genes in monocytic cells treated with interferon-gamma (IFN-gamma). Studies using recombinant (r) human proteins show that, unlike most other CXC chemokines, rHuMig and rIP-10 have no activity on neutrophils but appear to target lymphocytes specifically. rHuMig and rIP-10 are active as chemotactic factors for stimulated, but not for resting, T cells. Studies done in vitro and in vivo have shown that rHuMig and rIP-10 share additional activities, including inhibition of neovascularization, inhibition of hematopoietic progenitor cells, and anti-tumor effects. rHuMig and rIP-10 show reciprocal desensitization on activated T cells and have been demonstrated to share a receptor, CXCR3. The genes for both MuMig and Crg-2 are highly expressed in multiple tissues during experimental viral and protozoan infections in mice, but their patterns of expression differ. This suggests that the Migs and IP-10/Crg-2 may play roles in host defense and that, despite their similar activities assayed in vitro, Mig and IP-10/Crg-2 may serve non-redundant functions in vivo.

• Rajarathnam K, Kay CM, Clark-Lewis I, Sykes BD
• Characterization of quaternary structure of interleukin-8 and functional implications.
• Methods Enzymol. 1997; 287: 89-105

• Harada A
• [Chemokines and inflammatory diseases]
• Nihon Rinsho Meneki Gakkai Kaishi. 1997; 20: 477-80

• Wells TN, Peitsch MC
• The chemokine information source: identification and characterization of novel chemokines using the WorldWideWeb and expressed sequence tag databases.
• J Leukoc Biol. 1997; 61: 545-50
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• The chemokine superfamily is a large group of more than 30 small proteins. Many of these were originally identified because of their role in the selective recruitment and activation of leukocytes during inflammation. More recently, some of the chemokine receptors and ligands have been implicated in the mechanism of viral infection for primate lentiviruses such as HIV-1. From the original identification of interleukin-8 (IL-8; the most studied member of the superfamily), the number of new family members has mushroomed over the last few years. Two events have dramatically altered the speed at which sequence information concerning novel chemokines has become available to the scientific community. First, many groups have been obtaining large amounts of sequence information from cDNA libraries by sequencing the clones at random, generating expressed sequence tags (ESTs). Although these ESTs are relatively short, typically less than 500 bases, this amount of sequence is usually sufficient to obtain the entire open reading frame for chemokines. Second, there has been a rapid growth in the use of the WorldWideWeb by bioinformatics groups. The Web was originally set up by the European Centre for Particle Physics (CERN) in Geneva as a method of transferring data between collaborating groups throughout the world. It has enabled biologists throughout the world to have almost instantaneous access both to the databases containing the EST sequences and to the automated tools that are required for searching such databases. With such methods we have been able to rapidly identify more than 10 new human chemokines from public domain databases. In addition to the known categories of chemokines, which are named C, CC, and CXC based on the spacings of N-terminal cysteine residues, we have been able to identify the first member of a novel chemokine subfamily, with a novel CXXXC cysteine spacing. Furthermore, we can subdivide the CC chemokines into monocyte chemotactic protein and macrophage inflammatory protein families based on their sequence identity levels, but also their clustering on the human genome, as identified on other Web sites. The rapid availability of all this data has reduced the amount of time spent on conventional gene identification, enabling us to move quickly on to trying to understand the biology and physiological relevance of these molecules. The novel chemokine sequences obtained and alignments with existing members of the superfamily are now contained within a Chemokine Information Source on an open access server, allowing further searching of chemokine sequences and increasing the availability of such data to the scientific community.

• Harada A, Mukaida N, Matsushima K
• Interleukin 8 as a novel target for intervention therapy in acute inflammatory diseases.
• Mol Med Today. 1996; 2: 482-9
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• Aberrant production of interleukin 8 (IL-8) has been shown in various human inflammatory diseases. Recent investigations in animal models using either blocking antibodies against IL-8 or disruption of the gene encoding the IL-8 receptor have revealed the involvement of IL-8 in the recruitment of neutrophils and in neutrophil-associated tissue injury in acute inflammation. These studies suggest that IL-8 is a novel target to alleviate acute inflammation. This review describes the properties of IL-8 and discusses different therapeutic approaches to target IL-8, particularly the use of humanized monoclonal antibodies against IL-8 and inhibition of IL-8 gene transcription.

• Thompson SK, Veber DF, Jurewicz AJ, Peishoff CE, Lee JM, White JR
• Design and evaluation of small peptides mapping the exposed surface of IL-8.
• Int J Pept Protein Res. 1996; 47: 214-8
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• In an effort to determine which regions of IL-8 are involved in interactions with its receptors, eight peptides were designed to correspond to distinct exposed regions of the IL-8 monomer, using the proton NMR-derived structure of the dimer as a basis. The peptides were evaluated singularly, and as equimolar mixtures of two to six peptides, in an IL-8 receptor binding assay and found to have no binding interaction with either alpha or beta IL-8 receptor as single peptides or mixtures of two peptides. In contrast, one of these peptides having the sequence AVLPRSAKEL, which corresponds to the N-terminal 10 amino acid residues of the 77 amino acid form of IL-8, exhibited potent chemotactic activity in human neutrophils. These results indicate that there is no contiguous ligand that can be designed based on the NMR and X-ray determined structure of IL-8 and that there may be multiple receptors responsible for neutrophil activation and chemotaxis.

• Proost P, Wuyts A, van Damme J
• The role of chemokines in inflammation.
• Int J Clin Lab Res. 1996; 26: 211-23
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• Chemokines, together with adhesion molecules, cytokines, and proteases, are essential for the directional migration of leukocytes during normal and inflammatory processes. Interleukin-8 and monocyte chemotactic protein-1 are the best-characterized members of the C-X-C and C-C chemokine subfamilies, respectively. However, more than 20 human chemokines have been identified but are only partially characterized at the biological level. Chemokines are involved in chemotaxis of monocytes, lymphocytes, neutrophils, eosinophils, basophils, natural killer cells, dendritic cells, and endothelial cells. This review describes the chemokine subfamilies, the chemokine producer and target cells, their receptors, signal transduction mechanisms, and the role of chemokines during physiological and pathological conditions. More and more evidence points to a role for chemokines in chemotaxis-related phenomena, such as the expression of adhesion molecules, the secretion of proteinases, inhibition of apoptosis, hematopoiesis, and angiogenesis. Chemokines are also involved in diseases such as cancer (tumor regression and tumor metastasis), autoimmune diseases, and bacterial or viral infection.

• Sticht H et al.
• Structure and activity of a chimeric interleukin-8-melanoma-growth-stimulatory-activity protein.
• Eur J Biochem. 1996; 235: 26-35
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• A 72-amino-acid chimeric protein, Chi1, was constructed from the N-terminal part of interleukin 8, IL-8-(1-53), and the C-terminal part of melanoma growth stimulatory activity, MGSA-(54-72). Chi1 protein showed receptor-binding specificity and biological activity similar, but not identical to IL-8 and decidedly different from MGSA. The structure of Chi1 was determined in solution by two-dimensional NMR and molecular-dynamics calculations. The structure resembled the structures of MGSA and IL-8 closely, containing a triple-stranded beta-sheet in the IL-8 part and an amphipathic alpha-helix in the MGSA part. Chi1 formed dimers at millimolar concentrations via the first strand from the N-terminus, analogous to IL-8 and MGSA. In contrast to the latter molecules, however, the alpha-helix of Chi1 did not pack against the beta-sheet part, but was an independent structural element. This structural difference could be explained mainly by the modulation of hydrophobic interactions between the helix and the rest of the protein in Chi1 as compared to IL-8 and MGSA. It is concluded that tight helix packing is not required for receptor binding and biological activity of Chi1.

• Hoch RC, Schraufstatter IU, Cochrane CG
• In vivo, in vitro, and molecular aspects of interleukin-8 and the interleukin-8 receptors.
• J Lab Clin Med. 1996; 128: 134-45

• Clark-Lewis I et al.
• Structure-activity relationships of chemokines.
• J Leukoc Biol. 1995; 57: 703-11
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• Structural analysis of chemokines has revealed that the alpha/beta structural-fold is highly conserved among both the CXC and CC chemokine classes. Although dimerization and aggregation is often observed, the chemokines function as monomers. The critical receptor binding regions are in the NH2-terminal 20 residues of the protein and are the least ordered in solution. The flexible NH2-terminal region is the most critical receptor binding site and a second site also exists in the loop that follows the two disulfides. The well-ordered regions are not directly involved in receptor binding but, along with the disulfides, they provide a scaffold that determines the conformation of the sites that are critical for receptor binding. These general requirements for function are common to all the chemokines. For the CC chemokines, receptor activation and receptor binding regions are separate within the 10 residue NH2-terminal region. This has allowed identification of high affinity analogs that do not activate the receptor and are potent antagonists.

• Baggiolini M, Loetscher P, Moser B
• Interleukin-8 and the chemokine family.
• Int J Immunopharmacol. 1995; 17: 103-8
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• Two subfamilies of chemokines are distinguished depending on the arrangement of the first two of four conserved cysteines, which are either separated by one amino acid (CXC chemokines) or adjacent (CC chemokines). IL-8 and the other CXC chemokines act preferentially on neutrophils, while the CC chemokines (MCP-1, MCP-2, MCP-3, RANTES, MIP-1 alpha and MIP-1 beta) act on monocytes, but not neutrophils, and have additional activities toward basophil and eosinophil granulocytes, and T-lymphocytes. Several chemokine receptors have been identified, all of which belong to the seven-transmembrane-domain type and are coupled to G-proteins. The discovery of chemokines has provided the basis for the understanding of leukocyte recruitment and activation in inflammation and other disturbances of tissue homeostasis.

• Mukaida N, Harada A, Matsushima K
• A novel leukocyte chemotactic and activating cytokine, interleukin-8 (IL-8).
• Cancer Treat Res. 1995; 80: 261-86

• Kunkel SL, Lukacs NW, Strieter RM
• The role of interleukin-8 in the infectious process.
• Ann N Y Acad Sci. 1994; 730: 134-43

• Wuyts A, Proost P, Put W, Lenaerts JP, Paemen L, van Damme J
• Leukocyte recruitment by monocyte chemotactic proteins (MCPs) secreted by human phagocytes.
• J Immunol Methods. 1994; 174: 237-47
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• Phagocyte recruitment is an important immunological phenomenon in inflammation and cancer. A large family of selective chemotactic cytokines, designated chemokines, has recently emerged. Interleukin-8 (IL-8) is the prototype of such neutrophil activating factors, whereas MCP-1 is a well studied monocyte chemotactic protein. In vitro chemotactic assays were used to isolate and identify natural chemokines from mononuclear phagocytes and tumor cells. Additional new chemotactic proteins (MCP-2, MCP-3) attracting monocytes were also discovered by these methods. All chemokines are structurally related and show affinity for heparin. MCP-1, -2 and -3 have a comparable specific activity in monocyte chemotaxis assays. Specific and sensitive radioimmunoassays for MCP-1 and IL-8 were developed to study the regulation of their secretion by leukocytes. Monocytes or monocyte tumor cells produce MCP-1 and/or IL-8 in response to cytokines, virus, double stranded RNA, bacterial endotoxin, mitogen or phorbol ester. Granulocytes were found to secrete only minor amounts of MCP-1 and IL-8.

• Seow HF, Yoshimura T, Wood PR, Colditz IG
• Cloning, sequencing, expression and inflammatory activity in skin of ovine interleukin-8.
• Immunol Cell Biol. 1994; 72: 398-405
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• Ovine IL-8 (oIL-8) cDNA was obtained by probing a spleen cell cDNA library with human IL-8 (hIL-8) cDNA. The oIL-8 cDNA was 1434 base pairs long with a single open reading frame encoding a 101 amino acid precursor protein of relative molecular mass 11,268. The inferred amino acid sequence has 78, 82, 84 and 67% similarity with human, rabbit, porcine and guinea-pig IL-8, respectively. By analogy with the most prevalent form of hIL-8, a 72 amino acid form of oIL-8 was expressed as a fusion protein containing glutathione-S-transferase and purified by affinity chromatography on a glutathione-Sepharose column yielding 8 mg IL-8/L broth culture. The fusion protein lacked chemotactic activity for ovine neutrophils, whereas the 72 amino acid form of oIL-8 was equipotent with rhIL-8. At 6 and 24 h after intradermal injection of 10(-9) mol oIL-8, there was intense accumulation of neutrophils, and very mild accumulation of eosinophils, CD5, CD4 and T19 (a gamma delta TCR subset) cells but not CD8 cells. The availability of roIL-8 and its cDNA probes will permit the role of this important member of the IL-8 family of chemotactic cytokines to be determined in inflammatory diseases of sheep.

• Clubb RT, Omichinski JG, Clore GM, Gronenborn AM
• Mapping the binding surface of interleukin-8 complexes with an N-terminal fragment of the type 1 human interleukin-8 receptor.
• FEBS Lett. 1994; 338: 93-7
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• Interleukin-8 and its receptors are key mediators of immune and inflammatory responses. Heteronuclear NMR spectroscopy has been utilized to map the binding surface on interleukin-8 (IL-8) for an N-terminal fragment of the human Type-1 IL-8 receptor. A peptide corresponding to residues 1-40 of the IL-8 type 1 receptor (IL8-r1) was titrated into a sample of uniformly 15N-labeled IL-8. IL8-r1 binds to IL-8 with a dissociation constant of 170 +/- 50 microM assuming the peptide binds with a stoichiometry of one peptide per IL-8 monomer, exchanges rapidly (> 900 s-1) between free and bound states, and selectively perturbs the chemical environment of several IL-8 residues. The binding surface on IL-8 suggested by our results is comprised of residues in strand beta 3 of the beta-sheet (Glu48 to Cys50), the turn preceding beta 3 (Ser44), the C-terminal alpha-helix (Val61) and the irregular N-terminal loop region (Thr12, Lys15, Phe17, His18, Lys20 and Phe21). The IL-8 dimer appears to present two symmetrical binding surfaces for the IL8-r1 peptide, suggesting two receptor peptides may bind per dimer.

• Matsushima K
• [Properties of interleukin 8 and its correlation with inflammatory diseases and malignant neoplasia]
• Gan To Kagaku Ryoho. 1994; 21: 2525-32
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• Inflammation is a vital consequence of tissue injury caused by various reasons including invasion of foreign particles, infection with microorganisms, autoimmune responses, ischemia-reperfusion injury, and malignant neoplasia. In 1987, a major neutrophil chemotactic and activating factor, now called interleukin 8 (IL-8), was purified and molecularly cloned. In this article, general overview of IL-8 was made describing biochemical structure, regulation of production of IL-8, properties of the receptors for IL-8 and pathophysiological roles of IL-8 in inflammation.

• Kelvin DJ et al.
• Chemokines and serpentines: the molecular biology of chemokine receptors.
• J Leukoc Biol. 1993; 54: 604-12
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• Chemokines are pro-inflammatory molecules with a diverse array of biological and biochemical functions. These molecules induce the migration of a number of leukocyte subsets including monocytes, neutrophils, and T-cells. The recent cloning of the IL-8, GRO, and MIP-1 alpha chemokine receptors revealed that these glycoproteins belong to the serpentine family of seven transmembrane G-protein-coupled receptors. Other members of this family include the chemotactic receptors for fMLP and C5a, indicating that a common pathway for eliciting the directional migration of leukocytes is probably transduced via G proteins. Ligand binding to chemokine receptors is complex, featured by multiple chemokines binding to a single receptor and multiple receptors binding a specific ligand. Future directions in this field appear to be focused on the cloning of novel receptors and the identification of ligands for orphaned receptors.

• Bickel M
• The role of interleukin-8 in inflammation and mechanisms of regulation.
• J Periodontol. 1993; 64: 456-60
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• Interleukin-8 (IL-8) is a chemoattractant cytokine produced by a variety of tissue and blood cells. Unlike many other cytokines, it has a distinct target specificity for the neutrophil, with only weak effects on other blood cells. Interleukin-8 attracts and activates neutrophils in inflammatory regions. The importance of neutrophil functions has been recognized in periodontal disease for many years. Neutrophils represent the major population of immigrant cells in periodontitis. In diseases with neutrophil dysfunctions periodontal tissue is lost very rapidly. The response of neutrophils to IL-8 is characterized by migration of the cells, the release of granule enzymes, and other intra- and extracellular changes. Connective tissue constituents are efficiently degraded by neutrophil enzymes, released upon activation. Interleukin-8 is a member of the Interleukin-8 supergene family that includes other small chemotactic peptides with structural homology. It also shares with other cytokines DNA sequence features that suggest common regulatory pathways. In vivo intracutaneous application of IL-8 induces local exudation and a massive, long-lasting accumulation of neutrophils. Though IL-8 plays a role in the cytokine network, its major pathophysiological role lies in affecting neutrophils. This article presents a review of literature on the current knowledge of IL-8, its mechanisms of expression, and the effects it exerts on the neutrophil.

• Baggiolini M
• Novel aspects of inflammation: interleukin-8 and related chemotactic cytokines.
• Clin Investig. 1993; 71: 812-4

• Lu CY, Tang ZS
• [Interleukin-8 and inflammation]
• Sheng Li Ke Xue Jin Zhan. 1993; 24: 351-3

• Proost P, De Wolf-Peeters C, Conings R, Opdenakker G, Billiau A, Van Damme J
• Identification of a novel granulocyte chemotactic protein (GCP-2) from human tumor cells. In vitro and in vivo comparison with natural forms of GRO, IP-10, and IL-8.
• J Immunol. 1993; 150: 1000-10
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• Stimulated human osteosarcoma cells (MG-63) were used as a source of granulocyte chemotactic protein (GCP). In addition to the previously isolated GCP-1/IL-8, natural forms of GRO alpha, GRO gamma, and IP-10 were purified and identified by amino acid sequence analysis. Further, a novel GCP, GCP-2, was isolated in its natural form (6 kDa) and was found to be structurally related to the other members of the IL-8 family. GRO alpha, IP-10, and GCP-2 showed heterogeneity, in that several forms of each protein were recovered. These differed in truncation at the amino terminus. Reverse phase HPLC allowed us to separate four such different forms of GCP-2. These tumor-derived factors were compared in granulocyte activation and chemotaxis assays. IL-8 induced neutrophil gelatinase B release at 2 nM, but GRO alpha and GCP-2 showed a 5- to 10-fold lower specific activity. When the migration of granulocytes through polycarbonate micropore membranes was measured, GCP-2 and GRO alpha had a maximal chemotactic index comparable to that of IL-8. The minimal effective dose for GCP-2 and GRO alpha was 3 to 10 nM, whereas the specific activity of IL-8 was at least 10-fold higher. IP-10 was not active in this assay at doses up to 100 nM. Finally, in vivo chemotaxis was measured by using granulocyte recruitment in the rabbit skin model. After intradermal injection of 200 ng/site, GCP-2 provoked a significant granulocyte infiltration, albeit to a lesser extent than did IL-8 and GRO alpha. GCP-2 did not attract monocytes in vivo nor did it induce the cells in vitro to migrate or to produce enzyme. In conclusion, this study reveals a new member of the IL-8 family and shows that these related inflammatory mediators possess different potencies and efficacies towards granulocytes.

• Baggiolini M
• Chemotactic and inflammatory cytokines--CXC and CC proteins.
• Adv Exp Med Biol. 1993; 351: 1-11

• Hebert CA, Baker JB
• Interleukin-8: a review.
• Cancer Invest. 1993; 11: 743-50

• Schroder JM
• The neutrophil-activating peptide 1/interleukin 8, a novel neutrophil chemotactic cytokine.
• Arch Immunol Ther Exp (Warsz). 1992; 40: 23-31

• Michel G et al.
• Interleukin-8 receptor-mediated chemotaxis of normal human epidermal cells.
• FEBS Lett. 1992; 305: 241-3
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• Normal human keratinocytes show chemotactic behavior towards interleukin-8 (IL-8). Under physiological conditions this cytokine seems to be present in an equilibrium between monomeric and dimeric forms, as indicated by Western blotting data. Radioligand binding studies suggest that keratinocyte chemotaxis is mediated by receptors specific for IL-8 dimers. IL-8 receptor-specific mRNA can be detected in a keratinocyte cell line by polymerase chain reaction.

• Miller MD, Krangel MS
• Biology and biochemistry of the chemokines: a family of chemotactic and inflammatory cytokines.
• Crit Rev Immunol. 1992; 12: 17-46
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• Studies conducted in many laboratories over the past several years have resulted in the identification and initial characterization of a large superfamily of structurally and functionally related inflammatory cytokines. This superfamily currently includes 14 distinct members: platelet factor 4, beta-thromboglobulin, neutrophil activating peptide-1/interleukin-8, gro, IP-10, mig, ENA-78, macrophage inflammatory proteins-1 alpha and -1 beta, monocyte chemoattractant protein-1/JE, RANTES, HC-14, C-10, and I-309. Although numerous biological activities have been assigned to these molecules, a common theme is their ability to stimulate the chemotactic migration of distinct sets of cells, including neutrophils, monocytes, lymphocytes, and fibroblasts. Accumulating evidence indicates that these molecules play important roles in mediating cell recruitment and activation necessary for inflammation and the repair of tissue damage.

• Mukaida N, Harada A, Yasumoto K, Matsushima K
• Properties of pro-inflammatory cell type-specific leukocyte chemotactic cytokines, interleukin 8 (IL-8) and monocyte chemotactic and activating factor (MCAF).
• Microbiol Immunol. 1992; 36: 773-89

• Schroder JM, Christophers E
• The biology of NAP-1/IL-8, a neutrophil-activating cytokine.
• Immunol Ser. 1992; 57: 387-416

• Kuno K, Matsushima K
• [Leukocyte chemotactic and activating cytokines, interleukin 8 and MCAF]
• Nippon Rinsho. 1991; 49: 247-55

• Gronenborn AM, Clore GM
• Modeling the three-dimensional structure of the monocyte chemo-attractant and activating protein MCAF/MCP-1 on the basis of the solution structure of interleukin-8.
• Protein Eng. 1991; 4: 263-9
• Display abstract

• A model of the three-dimensional structure of the monocyte chemo-attractant and activating protein MCAF/MCP-1 is presented. The model is predicted based on the previously determined solution structure of interleukin-8 (IL-8/NAP-1) [Clore, G.M., Appella, E., Yamada, M., Matsushima, K. and Gronenborn, A.M. (1990) Biochemistry 29, 1689-1696]. Both proteins belong to a superfamily of cytokine proteins involved in cell-specific chemotaxis, host defense and the inflammatory response. The amino acid sequence identity between the two proteins is 24%. It is shown that the regular secondary structure elements of the parent structure can be retained in the modeled structure, such that the backbone hydrogen bonding pattern is very similar in the two structures. The polypeptide backbone is superimposable with an atomic r.m.s. difference of 0.9 A and all side chains can be modeled by transferring the parent side chain conformation to the new structure. Thus, the deduced structure, like the parent one, is a dimer and consists of a six-stranded antiparallel beta-sheet, formed by two three-stranded Greek keys, one from each monomer, upon which lie two symmetry-related antiparallel alpha-helices, approximately 24 A long and separated by approximately 14 A. All amino acid sequence changes can be accommodated within the parent polypeptide framework without major rearrangements. This is borne out by the fact that the IL-8/NAP-1 and modeled MCAF/MCP-1 structures have similar non-bonding energies. These results strongly suggest that both proteins and all other members of the superfamily most likely have the same tertiary structure.(ABSTRACT TRUNCATED AT 250 WORDS)

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