Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A family consisting of at least ten distinct novel 8-10 kd cytokines has been identified over the past 12 years. These cytokines exhibit from 20 to 45% homology in amino acid sequence, are probably all basic heparin-binding polypeptides, and have proinflammatory and reparative activities. The cDNA for these cytokines are characterized by conserved single open reading frames, typical signal sequences in the 5' region, and AT rich sequences in the 3' untranslated regions. Those human cytokines known as interleukin 8, platelet factor 4, beta thromboglobulin, IP-10 and melanoma growth stimulating factor or GRO can be assigned to a subfamily based on their location on chromosome 4 and unique structural features, whereas the second subset consisting of LD78, ACT-2, I-309, RANTES, and macrophage chemotactic and activating factor (MCAF) are all closely linked on human chromosome 17. In this review we have summarized and discussed the available information concerning the regulation and structure of the genes, the structure and biochemical properties of the polypeptide products, their receptors, signal transduction, cell sources, and in vitro as well as in vivo activities of these cytokines.
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PMID:Properties of the novel proinflammatory supergene "intercrine" cytokine family. 191 Jun 90

The platelet-derived growth factor-inducible gene JE was found to encode a 148-residue basic (pI = 10.4) secretory protein which shows striking similarity to the gene products of a family of small inducible genes (SIG), LD78, TCA3, IP10, 3-10C, 9E3/pCEF4, and gro/MGSA, and to several of the proteins secreted from platelet alpha-granules. Members of the SIG family have spatially conserved cysteine residues that vary in distance by only one amino acid residue as well as conserved proline residues at analogous sites. Hydrophilicity plots show alternating hydrophobic and hydrophilic domains which are similar for all members of the SIG family except IP10 and platelet factor 4, which show similarities to each other. The genomic organization of SIG family members is similar in the location of the splice junctions and the number of introns and exons, suggesting that they were derived from a common ancestor. The collective evidence suggests that a family of inducible cytokines, which are mitogenic or chemotactic, may act as intercellular coordinators of diverse responses designed to combat infection and promote the healing and regeneration of injured tissue.
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PMID:Platelet-derived growth factor-inducible gene JE is a member of a family of small inducible genes related to platelet factor 4. 291 Aug 58

Chemoattractants, including chemokines such as interleukin 8 (IL-8) and related proteins, activate leucocytes via seven-transmembrane-domain G-protein-coupled receptors. A cDNA for a novel receptor of this kind consisting of 327 amino acids was isolated from a human blood monocyte cDNA library. The polypeptide, termed monocyte-derived receptor 15 (MDR15), is an alternative form of the Burkitt's lymphoma receptor 1 (BLR1) encoded by a human Burkitt's lymphoma cDNA [Dobner, Wolf, Emrich and Lipp (1992) Eur. J. Immunol. 22, 2795-2799]. MDR15 and BLR1 cDNAs differ in the 5' region, where the open reading frame of MDR15 is shorter by 45 codons. Southern-blot analysis indicates that the two transcripts for MDR15 and BLR1 are encoded by the same gene. Northern-blot analysis using a probe that hybridizes with both mRNAs demonstrated high-level expression in chronic B-lymphoid leukaemia and non-Hodgkin's lymphoma cells and, to a lesser extent, peripheral blood monocytes and lymphocytes. Reverse transcription-PCR studies with MDR15- and BLR1-specific primers showed similar levels of transcripts for both receptors in RNA that was positive in Northern-blot analysis. MDR15 and BLR1 have high structural similarity to receptors for human IL-8 (about 40% amino acid identity) and other chemokines. However, none of a series of radiolabelled chemokines (IL-8, NAP-2, GRO alpha, PF4, IP10, MCP-1, MCP-2, MCP-3, I-309, RANTES and MIP-1 alpha) and other ligands (C3a and leukotriene B4) bound to Jurkat transfectants that stably expressed either MDR15 or BLR1 mRNA. The fact that MDR15 and BLR1 are expressed on leucocytes and show marked sequence similarity to chemokine receptors suggests the existence of as yet unidentified chemokines. Alternative transcript formation affecting the 5'-terminal part of the coding region may be a way to modify ligand-binding selectivity.
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PMID:Sequence variation of a novel heptahelical leucocyte receptor through alternative transcript formation. 763 92

The TCA3 gene encodes a proinflammatory cytokine related to IL-8 and MCP-1 (JE). TCA3 mRNA is produced by T cells in response to stimulation with Ag or Con A. Glycosylated and nonglycosylated forms of rTCA3 produced by transfected Chinese hamster ovary cells were purified. rTCA3 was used to immunize hamsters and produce mAb. Four mAb were characterized; each was specific for TCA3, failing to react with the closely related molecule MCP-1 (JE). Western blotting also demonstrated that all four mAb specifically recognize rTCA3, native TCA3 produced by activated mouse T cells, and the nonglycosylated TCA3 core protein. A sensitive and specific capture ELISA for TCA3 quantitation was developed, allowing measurement of TCA3 levels in the supernatants from activated murine splenocytes and T cell clones. In addition, two mAb demonstrated dose-dependent neutralization of TCA3 inflammatory activity. Thus, the results directly demonstrate that TCA3 is expressed in an activation-specific manner by mouse T cells. The data also provide characterization of mAb reagents specific for this new cytokine.
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PMID:Serologic analysis of a murine chemokine, TCA3. 767 29

We have tested the histamine releasing properties and priming abilities of a wide range of recombinant or purified cytokines and growth factors on the basophils of 20 subjects (10 atopic and 10 nonatopic). We found that monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 (MCAF/MCP-1), RANTES, human macrophage inflammatory protein-1 alpha and human inflammatory protein-1 beta, Connective tissue activating peptide III and Neutrophil Activating Peptide-2 (NAP-2) cause histamine release from basophils and are all members of the intercrine/chemokine family. MCAF/MCP-1 was as potent as anti-IgE or C5a and it is clearly the major contributor to histamine releasing factor activity. RANTES was the second major histamine releasing factor among the positive cytokines. Both MCAF/MCP-1 and RANTES are present in conditioned mononuclear cell media and can be separated using Mono Q anion exchange chromatography. We also demonstrated that RANTES has unusual chromatographic properties in spite of its isoelectric point of > 9.0 because it is largely found in peak-2 of the Mono Q column rather than peak-1 in which intercrines such as MCAF/MCP-1, IL-8, and connective tissue activating peptide III are found. All other cytokines and growth factors tested were negative, with the exception of IL-3, which caused histamine release in a subpopulation of subjects, and also primed basophils for release by anti-IgE. Other basophil primers for anti-IgE-dependent histamine release were IL-5, mast cell growth factor (c-kit ligand), and insulin-like growth factor II. Using specific neutralizing antibodies we have shown that MCAF/MCP-1, RANTES, and IL-3 contribute significantly to the activity found in mononuclear cell culture supernatants. Granulocyte-macrophage-CSF, IP-10, I-309, IL-7, IL-8, IL-9, IL-10, IL-11, IgE-binding factor, TNF-alpha, TGF-beta 1, fibroblast growth factor, epidermal growth factor, and endothelial cell growth factor were negative for direct histamine release and as primers of basophils. Our results indicate that cytokines belonging to the intercrine/chemokine family are major constituents of the activity known as "histamine releasing factor" found in MNC supernatants.
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PMID:Characterization of the human basophil response to cytokines, growth factors, and histamine releasing factors of the intercrine/chemokine family. 767 99

The murine beta-chemokine TCA3 was purified to homogeneity. The biologic activities of the purified glycoprotein were evaluated in vivo and in vitro. Mice injected i.p. with 1- to 100-ng purified rTCA3 exhibited a rapid influx of neutrophils and macrophages. Increased numbers of neutrophils and monocytes were observed in peripheral blood within 15 min and peak at 45 min. After 45 min neutrophil and macrophage levels were increased in the peritoneal exudate with peak levels occurring at 2 h, followed by a subsequent decline by 24 h. Inflammatory responses were induced in a dose-dependent fashion. The in vivo inflammatory responses were mirrored by the pattern of TCA3-induced chemotaxis in vitro. Neutrophils and macrophages responded to similar concentrations of TCA3 (3 x 10(-9) to 10(-8) M). Lymph node cells responded to other chemokines but did not migrate to TCA3. We also demonstrated that rTCA3 stimulates a transient increase in cytoplasmic free calcium in monocytic cells through a PTX-sensitive pathway. Cross-desensitization studies indicate that TCA3 acts independently of other beta-chemokines (MIP-1 alpha and RANTES) and the alpha-chemokine IL-8. Furthermore, TCA3 does not induce a Ca2 lux in cells transfected with cDNA for the C-C CKR-1 chemokine receptor, supporting the conclusion that there are distinct receptors for TCA3.
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PMID:Biologic activities of the murine beta-chemokine TCA3. 796 34

The chemokines are a family of immune mediators involved in a wide range of inflammatory processes, most importantly as chemoattractants of monocytes, neutrophils, lymphocytes, and fibroblasts to sites of inflammation. Nuclear magnetic resonance and x-ray crystallographic studies have shown that IL-8 and macrophage-inflammatory protein-1 beta (MIP-1 beta) form noncovalent dimers and that platelet factor-4 (PF-4) forms noncovalent dimers and tetramers, leading to the assumption that, as a family, the chemokines would form multimeric structures. In this study, we analyze the association states of the chemokines IL-8, monocyte chemoattractant protein-1 (MCP-1), and I-309, by using a combination of size exclusion HPLC, sedimentation equilibrium ultracentrifugation, and chemical cross-linking. We find that the association states of MCP-1 and IL-8 are characterized by an equilibrium between monomers and dimers: although dimers predominate at concentrations above 100 microM, these chemokines are almost exclusively monomeric at the nanomolar concentrations at which they display maximal chemotactic activity. I-309, by contrast, remains a monomer at all concentrations tested. I-309 contains two additional cysteine residues (C26 and C68) that are not found in any other members of the chemokine family. We used cyanogen bromide and trypsin digestion strategies to demonstrate that these two residues are linked in a unique intramolecular disulfide bond. Furthermore, by using site-directed mutagenesis, we show that the integrity of this bond is crucial for protein secretion.
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PMID:The chemokines IL-8, monocyte chemoattractant protein-1, and I-309 are monomers at physiologically relevant concentrations. 807 76

Specific receptors for the beta-chemokine TCA3 have been identified on mouse monocyte/macrophage cell lines and on mouse mesangial cells. Using Scatchard plot analysis with 125I-labeled TCA3, a single high-affinity receptor (3-4 nM) was identified. Cells of the monocyte lineage express 1,400 to 8,600 TCA3 binding sites, while mesangial cells display 40,000 to 49,000 sites/cell. Competitive inhibition studies indicated that the TCA3 receptor is unique, although MCP-1, IL-8, and RANTES were weak competitors of TCA3 binding. We also established the functional activity of TCA3 and other chemokines on primary cultures of mouse mesangial cells. TCA3 treatment induces increased mesangial cell adhesiveness to fibronectin. TCA3 is also a chemoattractant for mesangial cells. In addition, TCA3 treatment stimulates [3H]thymidine uptake by mesangial cells. The combined results indicate that TCA3 and other chemokines interact with a broader range of target cells than previously considered.
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PMID:Beta-chemokine TCA3 binds to mesangial cells and induces adhesion, chemotaxis, and proliferation. 854 28

We have previously reported that cytokines such as IL-9, IL-4, and IL-6 protect murine thymic lymphoma cell lines against dexamethasone-induced apoptosis. A similar activity, which could not be ascribed to any of these factors, was found in a number of human T cell supernatants that enabled mouse BW5147 thymic lymphoma not only to escape apoptosis but also to maintain proliferation. The protein responsible for this activity was purified to homogeneity from the culture medium of activated leukemic T cells and was found to be identical with the I-309 chemokine. Half-maximal anti-apoptotic activity was obtained with approximately 1 ng/ml, a concentration considerably lower than that required for the monocyte chemotactic activity of this molecule, as measured on THP-1 cells. The purified I-309 also improved the survival of two other mouse thymic lymphoma cell lines. This activity was as potent as that of IL-9, which was the strongest anti-apoptotic factor found to date for these cells. Similar results were obtained for BW5147 cells with recombinant I-309 and with T cell activation gene-3, the murine homologue of I-309, but not with other members of the chemokine family, including IL-8, neutrophil-activating peptide-2, granulocyte chemotactic protein-2, macrophage inflammatory protein-1a, RANTES (regulated upon activation, normal T cell expressed and secreted), monocyte chemotactic protein-1 (MCP-1), and MCP-2. MCP-3, however, showed a minor, but significant effect in this model. Unlike that of IL-9, the activity of I-309 was completely inhibited in the presence of pertussis toxin, indicating the involvement of a G protein in this process.
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PMID:I-309/T cell activation gene-3 chemokine protects murine T cell lymphomas against dexamethasone-induced apoptosis. 880 59

Cytokines with immunostimulating effects have the capacity to induce tumor immunity in animal models, whereas some cytokines interfere with tumor growth based on their angiostatic effects. Despite these capabilities, cytokines, such as IFN-, IFN-, tumor necrosis factor, interleukin (IL)-1, and IL-2, have had limited clinical efficacy and many undesirable side effects. In preclinical models, cytokines can even promote tumor growth and increase metastatic spread. Although chemokines have had limited clinical evaluation, studies of animal models show that they can also have tumor-suppressive or tumor-enhancing effects. In mice, chemokines, such as IP-10, RANTES, and TCA3, have resulted in tumor regression and immunity to subsequent tumor challenge. Those chemokines that are angiostatic (e.g., PF4, IP-10, and MIG) can also induce tumor regression by reducing the tumor blood supply. Conversely, IL-8, which is angiogenic, can promote tumor growth. Our studies show that nasopharyngeal cell line cells (FADU) show a chemotactic as well as a proliferative response to MCP-1. In addition, a variant murine T cell lymphoma cell line Esb-MP, unlike the parental variant Esb, was selectively chemoattracted by murine MCP-1/JE. When injected s.c. into mice, the Esb-MP variant metastasized to the kidney with much higher frequency than the Esb variant. Both cultured kidneys from normal mice and a mesangial cell line constitutively produced chemoattractants that acted on Esb-MP but not Esb parental cells. Purification to homogeneity of these chemoattractants led to the identification of RANTES and JE. These results demonstrate that some chemokines may promote tumor growth and organ-specific metastatic spread of those tumors that have adapted and become responsive to chemokines. Finally, tumors appear to use numerous adaptive mechanisms to subvert and suppress the immune system. More effective therapy with cytokines and chemokines will require better characterization of the means by which tumors develop resistance to cytokines and overcome the immune system. Only then can we develop appropriate therapeutic approaches to antagonize cancer-induced immunosuppression.
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PMID:Prospects for cytokine and chemokine biotherapy. 1006 74


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