UNIPROT:P10145 - FACTA Search

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Query: UNIPROT:P10145 (IL-8)
23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 human neutrophil-activating peptide 2 (NAP-2) belongs to the so-called beta-thromboglobulin/interleukin 8-family of chemotactic and reparative host defense cytokines. NAP-2 represents one of several N-terminally truncated cleavage products that originate from platelet-derived precursor molecules through proteolytic processing. Among these homologous isoforms that are comprised as beta-thromboglobulin antigen (beta-TG Ag), NAP-2 is recognized as the major component, having the highest potential for the activation of polymorphonuclear neutrophils (PMN). We now present evidence that there exists a second molecular form of NAP-2 with even higher biological activity. This novel isoform was detected in concentrates of culture supernatants from peripheral blood mononuclear cells, and could be separated from authentic NAP-2 by several steps of column chromatography. It had an N-terminus identical to that of NAP-2 but was biochemically different as indicated by its slightly lower molecular weight and a higher isoelectric point. To examine our hypothesis that the polypeptide represented a C-terminally truncated variant of NAP-2, we prepared synthetic peptides that were used for the induction and characterization of two rabbit antibody fractions, directed against different and defined epitopes within the C-terminal alpha-helix of the NAP-2 molecule. Comparison of reactivity patterns of these antibodies in Western blots as well as in a NAP-2 biological assay (PMN degranulation assay) confirmed that the variant NAP-2 was truncated at its C-terminus by at least one and by maximally three residues. The specific activity of the truncated polypeptide was estimated to be about four-fold higher than that of authentic NAP-2, as determined in the PMN degranulation assay. Thus, proteolytic modification at the C-terminus appears to play a role in the regulation of NAP-2-biological activity.
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PMID:A novel molecular variant of the neutrophil-activating peptide NAP-2 with enhanced biological activity is truncated at the C-terminus: identification by antibodies with defined epitope specificity. 768 53

Interleukin-8 (IL-8) and the structurally related cytokines neutrophil-activating peptide-2 (NAP-2) and GRO alpha are powerful chemotactic agents for human neutrophils. Although these three chemokines act by binding to overlapping but not identical receptor subsets, the data available to date have stressed the similarities in their mechanisms of action. The present studies were undertaken to further our understanding of the signal transduction mechanisms associated with these neutrophil agonists. IL-8, NAP-2, and GRO alpha stimulated similar increases in the level of cytoplasmic free calcium. They were also shown to stimulate qualitatively similar increases in the levels of protein tyrosine phosphorylation. In contrast, only IL-8 enhanced the formation of phosphatidylethanol (PEt), the product catalyzed by phospholipase D (PLD) in the presence of ethanol. The formation of PEt stimulated by IL-8 was inhibited by pertussis toxin and the tyrosine kinase inhibitors erbstatin and herbimycin A. The ability of IL-8 to stimulate the activity of PLD was additively enhanced, or primed, by cytochalasin B and by tumor necrosis factor alpha. Although all three chemokines increased the level of free cytoplasmic calcium to the same extent, IL-8 was significantly more potent than either NAP-2 or GRO alpha with respect to its ability to enhance CD11b expression and to stimulate chemotactic and oxidative responses. The differences between IL-8, NAP-2, and GRO alpha in their ability to stimulate PLD is likely to be related to their respective binding affinities for the two IL-8 receptors (IL-8R-A and IL-8R-B). These results suggest that the signalling pathways activated by IL-8R-A and IL-8R-B diverge at a step preceding the activation of PLD.
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PMID:Diverging signal transduction pathways activated by interleukin-8 and related chemokines in human neutrophils: interleukin-8, but not NAP-2 or GRO alpha, stimulates phospholipase D activity. 781 7

The proinflammatory cytokine and potent chemoattractant IL-8 is involved in regulation of infectious or inflammatory processes. Human vascular endothelial cells (EC) and smooth muscle cells (SMC) probably contribute to these responses by recognition and/or production of rIL-8. We demonstrate here in competitive binding studies with radiolabeled rIL-8 that EC and fibroblasts, but not SMC, specifically bind IL-8 with low affinity. The binding was not saturated by ligand concentrations up to 80 nM 125I-rIL-8. Unlabeled neutrophil-activating peptide-2 competed the binding of 125I-rIL-8, although less potently than unlabeled rIL-8, as reported previously for polymorphonuclear neutrophils. In contrast, connective tissue-activating peptide III, platelet factor 4, or lysozyme did not reduce binding of 125I-rIL-8 to EC or fibroblasts. In accordance with these binding studies, EC and fibroblasts, but not SMC, expressed human IL-8 receptor type I mRNA. Neither cell type expressed mRNA for IL-8 receptor type II. Stimulation with IL-1 alpha or LPS did not alter the results obtained in PCR or binding studies. Although SMC did not express specific binding sites for IL-8, Western blot experiments showed that IL-1 alpha-, TNF-, or LPS-stimulated SMC released two major immunoreactive isoforms of IL-8 in a time- and dose-dependent manner. The m.w. were similar to IL-8 isoforms released by EC or mononuclear cells. The differential capacity of EC and SMC to produce IL-8 and express IL-8 binding sites indicates that vascular cell-derived IL-8 may contribute to differential regulation of infectious and inflammatory responses in the vessel wall.
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PMID:IL-8 specifically binds to endothelial but not to smooth muscle cells. 786 4

The connective tissue-activating peptide III (CTAP-III), which is released from activated platelets, represents an inactive precursor of the chemokine neutrophil-activating peptide 2 (NAP-2). Leukocytes and leukocyte-derived proteases have been found to convert CTAP-III into NAP-2 by proteolytic cleavage at the N terminus. We demonstrate here that rapid and efficient formation of NAP-2 is mediated by neutrophil granulocytes (PMN) but not by monocytes or lymphocytes. However, as seen in a degranulation assay, neutrophils processing CTAP-III did not become activated by the generated NAP-2 and even exhibited decreased responsiveness to high doses of NAP-2 or IL-8, but not to FMLP. The desensitizing effect, being maximal already after 5 min of preincubation with CTAP-III, was not mediated through binding of the precursor to specific receptors but correlated with the rapid down-modulation of common NAP-2/IL-8 high affinity binding sites. A similar functional and receptor desensitization was observed in PMN pre-exposed to nonstimulatory doses of NAP-2. Specific inhibition of the CTAP-III-cleaving enzyme by the serine protease inhibitor aprotinin abrogated the CTAP-III, but not the NAP-2-mediated effects. Desensitization of PMN by CTAP-III was due to NAP-2 generated by proteolytic truncation of CTAP-III. Our results suggest that CTAP-III may regulate PMN activation by protecting processing cells from premature activation.
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PMID:Connective tissue-activating peptide III desensitizes chemokine receptors on neutrophils. Requirement for proteolytic formation of the neutrophil-activating peptide 2. 798 67

IL-8 and the neutrophil-activating peptide 2 (NAP-2) are members of the chemokine family of host defense cytokines. Although IL-8 was shown to interact with two different high affinity receptors on polymorphonuclear neutrophil granulocytes (PMN), direct demonstration of specific binding sites for NAP-2 is difficult, because the NAP-2 molecule lacks iodinable side chains. Here we present a modified labeling procedure for the chemokine that does not affect its biologic activity. The 125I-labeled NAP-2 specifically bound to PMN with two different affinities (KD = 0.65 and 22.4 nM). We observed complete cross-competition of unlabeled IL-8 with 125I-labeled-NAP-2 and of unlabeled NAP-2 with 125I-labeled IL-8, indicating the absence of monospecific binding sites for either chemokine. However, in contrast to former work by others, the total number of accessible sites was considerably lower for NAP-2 (13,000/cell) than for IL-8 (59,000/cell). In addition, PMN prepared from heparinized blood expressed significantly more receptors for NAP-2 than cells prepared from citrated blood, whereas receptor numbers for IL-8 were unchanged. Desensitization experiments suggested a regulatory role for the NAP-2 high affinity site. Short-term priming of PMN with a nonstimulatory dose of NAP-2 (or MGSA) but not with IL-8 led to drastic down-regulation of the subsequent degranulation response, challenged by higher dosages of NAP-2, MGSA, or IL-8. Reduced functional responsiveness of cells correlated with the rapid down-regulation and internalization of NAP-2 and IL-8 high affinity binding sites. Thus, our data indicate that chemokines could mediate by individual modes of interaction with common receptor's different biologic functions.
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PMID:Neutrophil-activating peptides NAP-2 and IL-8 bind to the same sites on neutrophils but interact in different ways. Discrepancies in binding affinities, receptor densities, and biologic effects. 781 96

IL-8 mediates migration and activation of neutrophils. This study describes the functional and ligand binding specificity of the human intercrine peptides IL-8, neutrophil-activating peptide 2 (NAP-2), melanoma growth stimulatory activity (GRO), and platelet factor 4 (PF4) to rabbit neutrophils and mammalian cell lines transfected with rabbit IL-8 receptor cDNA (F3R). Rabbit neutrophil membranes bound 125I-labeled IL-8 and 125I-labeled NAP-2 but did not bind 125I-labeled GRO or 125I-labeled PF4. Rabbit neutrophils mobilized intracellular Ca2+ in response to IL-8 and NAP-2 but not to GRO or PF4. Monkey kidney cells (COS-7) and hamster lung fibroblasts (CCL-39) were transiently and stably transfected with the rabbit neutrophil IL-8 receptor F3R cDNA. COS-7 cells transfected with F3R cDNA bound 125I-labeled IL-8 but did not bind other IL-8-related peptides such as 125I-labeled NAP-2, 125I-labeled GRO, or 125I-labeled PF4. Furthermore, bound 125I-labeled IL-8 was only displaced by unlabeled IL-8 but not by unlabeled NAP-2, GRO alpha, or PF4. Consistent with this observation, stably transfected CCL 39 cells expressing F3R cDNA mobilized Ca2+ only in response to IL-8. We conclude that F3R cDNA encodes a functional IL-8 receptor isotype with strict ligand binding specificity for IL-8, that rabbit neutrophils do not bind human GRO alpha, and it is suggested that rabbit neutrophils contain in addition to the F3R protein another IL-8 receptor isotype with broad ligand specificity or a distinct NAP-2 receptor.
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PMID:Functional and ligand binding specificity of the rabbit neutrophil IL-8 receptor. 813 60

Interleukin-8 (IL-8) mediates the transendothelial migration and activation of neutrophils to the site of inflammation. Two human IL-8 receptor isotype (A and B) and one rabbit IL-8 receptor isotype (A) cDNAs have been previously cloned and characterized on the basis of their pharmacological profile. Human and rabbit IL-8 receptor subtype A binds IL-8 and structurally related peptide melanoma growth-stimulating activity (MGSA) and neutrophil-activating peptide-2 (NAP-2) according to the following affinity binding profile: IL-8 >>> MGSA > NAP-2, whereas the human IL-8 receptor subtype B profile is IL-8 = MGSA > NAP-2 (LaRosa, G., Thomas, K. M., Kaufmann, M., Mark, R., White, M., Taylor, L., Gray, G., Witt, D., and Navarro, J. (1992) J. Biol. Chem. 267, 25402-25406). In this study, we isolated a cDNA clone (5B1a) from a rabbit neutrophil library encoding a G-protein-coupled receptor of the interleukin-8 receptor family. The 5B1a clone encodes a 358-amino acid protein exhibiting 80% amino acid identity to the human IL-8 receptor B, 74% to the rabbit IL-8 receptor A, and 73% to the human IL-8 receptor A. Tissue distribution by Northern blot analysis reveals that the 5B1a mRNA is expressed preferentially in neutrophils. In contrast to previously described IL-8 receptors, the 5B1a receptor exhibited specific 125I-IL-8 binding with a novel affinity binding profile of IL-8 >> NAP-2 > MGSA. The corresponding apparent Ki values for IL-8, NAP-2, and MGSA were 4, 120, and 320 nM, respectively. IL-8 induced intracellular calcium mobilization and desensitization in Chinese hamster ovary cells stably transfected with 5B1a, indicating that this cDNA encodes a functional IL-8 receptor. Sequence analysis of the 5B1a protein with other IL-8 receptor subtypes within the framework of their pharmacological profile reveals putative structural motifs that may correspond to the ligand binding site of the IL-8 receptor.
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PMID:Molecular characterization of a novel rabbit interleukin-8 receptor isotype. 817 42

The expression and regulation of seven human members of a family of related cytokines, which play a role as effectors of inflammation, were analysed in hemopoietic cells and in fibroblasts. In T lymphocytes all genes: platelet basic protein (PBP); platelet factor 4 (PF-4); IL-8/NAP-1; IP-10; GRO; pAT464 and pAT744 were induced by stimulation with phytohemagglutinin and phorbol 12-myristate 13-acetate (PHA/PMA). In contrast to T cells, only some of the genes were induced upon terminal differentiation of pro-monocytic cells and upon serum stimulation of resting fibroblasts. This distinct expression indicates functional differences of the individual proteins. The expression of inflammatory mediators in fibroblasts suggests the involvement of these cells in inflammatory reactions.
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PMID:Cell type specific expression of members of the IL-8/NAP-1 gene family. 833 26

Two cDNAs coding for distinct interleukin 8 (IL-8) receptors, IL-8R1 [Murphy and Tiffany (1991) Science 253, 1280-1283] and IL-8R2 [Holmes, Lee, Kuang, Rice and Wood (1991) Science 253, 1278-1280] have been reported, and biochemical studies on human neutrophils have revealed two proteins (p70 and p44) that bind IL-8 with high affinity [Moser, Schumacher, von Tscharner, Clark-Lewis and Baggiolini (1991), J. Biol. Chem. 266, 10666-10671]. We have cloned the cDNA coding for IL-8R1 from a library of differentiated HL-60 cells. Transfection of this cDNA into Jurkat cells resulted in the expression of high-affinity binding for IL-8 and two related cytokines, GRO alpha and neutrophil-activating peptide 2 (Kd 0.5-1.0 nM). Northern-blot analysis with the IL-8R1 cDNA as probe revealed abundant expression of transcripts of different size in human neutrophils and low-level expression of a single RNA species in HL-60 cells differentiated with dimethyl sulphoxide and retinoic acid. Because of the extensive nucleotide sequence similarity of the cDNAs for IL-8R1 and IL-8R2, the reverse-transcription PCR method was used for analysis of RNA expression in myeloid and lymphoid cells, 19 cell lines established from human primary melanomas or metastases, two melanocyte and one fibroblast cell lines. IL-8R1 mRNA transcripts were expressed at high levels in neutrophils, and to a lesser extent in blood monocytes and the myeloid cell lines, HL-60 and AML 193, but were not found in THP-1 cells, lymphocytes and Jurkat cells. IL-8R2 mRNA transcripts, by contrast, were found in all blood cells and related cell lines, as well as in all melanoma, melanocyte and fibroblast cell lines tested. As for IL-8R1, IL-8R2 mRNA expression was highest in neutrophils. These results suggest that IL-8R1 and IL-8R2 may both be involved in neutrophil activation by IL-8 and related cytokines, and presumably correspond to p70 and p44, the receptors that were identified biochemically. Possible IL-8 functions on lymphocytes and melanoma cells, e.g. chemotaxis and proliferation, must be independent of IL-8R1 and may be mediated by IL-8R2.
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PMID:Expression of transcripts for two interleukin 8 receptors in human phagocytes, lymphocytes and melanoma cells. 836 81

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