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

Interleukin-8 (IL-8) is a key mediator in the migration of neutrophils from the circulation to the site of inflammation in the tissue. IL-8 is secreted by many cell types in response to proinflammatory stimuli such as interleukin 1, tumor necrosis factor, and lipopolysaccharide and is a potent chemoattractant and activator of neutrophils. Neutrophil activating peptide-2 (NAP-2) and melanoma growth-stimulatory activity (MGSA/GRO) are structurally and functionally related to IL-8 and, like IL-8, bind to specific G protein-coupled receptors on neutrophils. In the present study two closely related cloned IL-8 receptor subtypes are characterized by expression of the cDNA clones in monkey kidney cells (COS-7) or chinese hamster ovary cells and analysis of their ligand binding profiles. Both receptor subtypes bind 125I-labeled IL-8 with similar high affinity, however, the F3R receptor binds IL-8 exclusively, while the 4Ab receptor binds both IL-8 and MGSA/GRO with high affinity and NAP-2 with lesser affinity. Furthermore, we demonstrate with the use of intersubtype chimeric receptors that the specificity of ligand binding to both IL-8 receptor subtypes is dictated by the heterogeneous NH2-terminal domain. The F3R receptor is representative of a restricted IL-8 receptor subtype, and 4Ab represents a nonrestricted receptor subtype. It is proposed that these subtypes be named IL-8 receptors alpha and beta, respectively.
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PMID:Amino terminus of the interleukin-8 receptor is a major determinant of receptor subtype specificity. 128 Nov 58

Thrombin stimulation of human platelets results in the release of a preformed proteinaceous human eosinophil (Eo)-chemotactic activity. By the use of different high-performance liquid chromatography techniques, two Eo-chemotactic polypeptides (EoCPs), tentatively termed EoCP-1 and EoCP-2, were purified to homogeneity. Upon SDS-PAGE analysis, these chemotaxins showed molecular masses near 8 kD. NH2-terminal amino acid sequence analysis revealed identical sequences for both EoCP-1 and EoCP-2, which are also identical to that of RANTES, a cytokine that structurally belongs to the interleukin 8 superfamily of leukocyte selective attractants, and that is known to be a "memory-type" T lymphocyte-selective attractant. In the major Eo chemotaxin, EoCP-1, the residues 4 and 5, which in EoCP-2 were found to be serine residues, could not be identified. Electrospray mass spectrometry (ESP-MS) of EoCPs revealed for EoCP-2 a molecular mass of 7,862.8 +/- 1.1 daltons, which is 15.8 mass units higher than the calculated value of RANTES, indicating that EoCP-2 is identical to the full-length cytokine, and oxygenation, probably at methionine residue number 64, has taken place. Upon ESP-MS, EoCP-1 showed an average molecular mass of 8,355 +/- 10 daltons, suggesting O-glycosylation at these serine residues. Both natural forms of RANTES showed strong Eo-chemotactic activity (ED50 = 2 nM) with optimal chemotactic migration at concentrations near 10 nM, however, there were no significant migratory responses with human neutrophils. Chemotactic activity of RANTES for human Eos could be confirmed using recombinant material, which has been found to be as active as the natural forms. Since RANTES gene expression has been detected in activated T lymphocytes, and recombinant RANTES was shown to be a "memory" T lymphocyte-selective attractant, it is now tempting to speculate about an important role of RANTES in clinical situations such as allergene-induced late-phase skin reactions in atopic subjects or asthma, where in affected tissues both memory T cells and Eos are characteristic.
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PMID:Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils. 138 64

In the present studies, the mechanisms underlying the inhibitory actions of lipocortin-1 on the pyrogenic and thermogenic properties of cytokines were investigated. Central (icv) injection of corticotropin-releasing factor (CRF, 4.7 micrograms) or the recombinant cytokines interleukin (IL)-1 alpha (50 ng), IL-1 beta (5 ng), IL-6 (20 ng), IL-8 (20 ng), or tumor necrosis factor-alpha (TNF-alpha, 1 microgram) in conscious rats produced significant increases in resting oxygen consumption (VO2, 13-26%) and colonic temperature (0.7-1.6 degrees C) within 2 h postinjection. Administration (icv) of a recombinant fragment (NH2-terminus, 1-188 amino acids) of human lipocortin-1 (1.2 micrograms) produced small increases in VO2 (< 5%) and body temperature (< 0.3 degrees C). Pretreatment (-5 min) with lipocortin-1 significantly attenuated the thermogenic and pyrogenic effects of centrally injected IL-1 beta (80% inhibition), IL-6 (60%), IL-8 (80%), or CRF (60%). However, pretreatment with lipocortin-1 failed to modify the actions of IL-1 alpha or TNF-alpha. We have previously demonstrated that the pyrogenic and thermogenic effects of IL-1 beta, IL-6, and IL-8 are dependent on the central actions of CRF, whereas IL-1 alpha and TNF-alpha act independently of CRF. Fever and thermogenesis induced by all of these cytokines (with the exception of IL-8) can also be prevented by administration of a cyclooxygenase inhibitor. The data presented here suggest that the potent antipyretic effects of lipocortin-1 may result from inhibition of the release or actions of CRF rather than modulation of eicosanoid synthesis.
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PMID:Inhibition of central actions of cytokines on fever and thermogenesis by lipocortin-1 involves CRF. 141 82

Cytokine-stimulated human osteosarcoma cells (MG-63) secrete several related chemotactic factors, including the neutrophil-activating protein interleukin 8 (IL-8) and the monocyte chemotactic protein (MCP)-1. We describe the isolation and characterization of two novel monocyte chemotactic factors from this tumor cell line. Although these proteins copurified with MCP-1 and IL-8 on heparin-Sepharose, they could be separated by cation-exchange fast protein liquid chromatography and reverse-phase high-performance liquid chromatography. The corresponding 7.5- and 11-kD proteins were NH2-terminally blocked but were identified by sequencing peptide fragments. They showed a primary structure mostly related to that of MCP-1 and were therefore designated MCP-2 and MCP-3, respectively. These molecules can be classified in a subfamily of proinflammatory proteins characterized by the conservation of cysteine residues. MCP-2 and MCP-3 are also functionally related to MCP-1 because they specifically attract monocytes, but not neutrophils, in vitro. The chemotactic potency (specific activity) was comparable for all three MCPs. Intradermal injection of these proteins in rabbits resulted in selective monocyte recruitment in vivo. Since tumor cells are good producers of leukocyte chemotactic factors, it could be questioned whether these molecules can indirectly control tumor growth by attracting leukocytes or whether they rather promote invasion by the secretion of proteases from the attracted cells.
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PMID:Structural and functional identification of two human, tumor-derived monocyte chemotactic proteins (MCP-2 and MCP-3) belonging to the chemokine family. 161 66

Neutrophil accumulation in the epidermis is a histologic characteristic of psoriasis. We addressed the question: What is the major protein-like chemotactic principle responsible for neutrophil accumulation? Purification of proteinaceous neutrophil chemoattractants from extracts obtained from psoriatic scales by multistep high-performance liquid chromatography (HPLC) yielded three biochemically distinct polypeptides with potent neutrophil chemotactic activity. Aminoterminal amino acid sequence analysis of the quantitatively major neutrophil attractant revealed the sequence ELRXQXIKTYSK, which is identical to that of a 69 residue form of neutrophil-activating peptide-1/interleukin 8 (NAP-1/IL-8). The second major attractant showed the sequence XXVATELRXQXL . . ., which is identical to that of the gene product of the oncogene "gro" as well as "melanoma growth stimulatory activity, MGSA," whereas the third and minor neutrophil chemotaxin has an NH2-terminal sequence identical with NAP-1/IL-8. Estimation of NAP-1/IL-8-related proteins and gro/MGSA by HPLC combined with bioassay revealed a mean of 3.3 +/- 1.7 ng NAP-1/IL-8-related proteins (n = 11) and 3.2 +/- 1.9 ng gro/MGSA (n = 11) per 1 mg psoriatic scales. In normal heel callus (n = 8), these neutrophil attractants were found at concentrations below 0.02 +/- 0.01 ng/mg. The finding of more than 150-times increased amounts of both NAP-1/IL-8 and gro/MGSA in lesional psoriasis material suggest that these mitogenic as well as neutrophil- and lymphocyte-chemotactic compounds may play an important role in the pathogenesis of psoriasis.
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PMID:Neutrophil-activating proteins in psoriasis. 173 89

Interleukin-8 (IL-8) is an inflammatory mediator that stimulates neutrophil migration and functional activation. Analogs of human IL-8 were chemically synthesized, purified, and compared with the full-length 72-residue synthetic IL-8 for their ability to stimulate neutrophil chemotaxis and exocytosis as measured by assaying for release of elastase, as well as their binding to specific receptors in competition assays. Analogs corresponding to the less abundant natural forms, 3-72, 4-72, and 77-residue IL-8, were evaluated and the 3-72 and 4-72 had 2-5-fold higher potencies, whereas the 77-residue IL-8 was 2-fold less potent. A major finding was that NH2-terminal residues 4, 5, and 6 were absolutely essential for IL-8 activity and receptor binding. Quantitative dissociation of elastase release and chemotaxis activity was detected with 5-72, which compared with 1-72, was 80-fold less potent in the elastase assay, but was only slightly less potent in stimulating chemotaxis. IL-8 6-72 lacked all the biological activities tested but had detectable receptor binding activity. The NH2-terminal peptide, AVLPRSAKEL, lacked activity and receptor binding, suggesting that the NH2-terminal region alone is not sufficient for function. Comparison of analogs shortened at the COOH terminus showed that potency was progressively reduced as the COOH-terminal residues were excluded. However activity was retained in an analog (1-51) with the entire COOH-terminal alpha helix and beta turn missing. A peptide corresponding to the COOH-terminal 22 residues, although inactive alone, synergized with the 1-51 analog in stimulating elastase release. The results suggest that the NH2-terminal residues 4, 5, and 6, which are disordered in the IL-8 solution structure, are directly involved in receptor binding, but the COOH-terminal alpha helix is probably important for stabilizing the three-dimensional structure. Other regions within residues 7-51 are also functionally important.
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PMID:Structure-activity relationships of interleukin-8 determined using chemically synthesized analogs. Critical role of NH2-terminal residues and evidence for uncoupling of neutrophil chemotaxis, exocytosis, and receptor binding activities. 174 11

Neutrophil-activating protein-2 (NAP-2), an NH2-terminally processed form of the platelet-release product beta thromboglobulin (beta TG), was purified to homogeneity from stimulated human blood leukocytes. In the presence of a vasodilator substance (PGE2, CGRP) picomolar (pmol/l) amounts of NAP-2 induced neutrophil accumulation and plasma leakage on intradermal injection in rabbit skin, whereas the longer forms, beta TG itself and connective tissue-activating peptide III (CTAP-III), had no such effect. NAP-2-induced increased in microvascular permeability was neutrophil dependent and fast in onset, with a half-life of 65 to 75 minutes, comparable to that previously reported for the structural-related neutrophil-activating protein-1/interleukin-8 (NAP-1/IL-8). However NAP-2 showed a lower potency in that more protein was needed to provoke skin reactivity. Nevertheless the finding that a platelet release product can elicit neutrophil-mediated inflammation further narrows the gap between thrombotic events and inflammatory disorders.
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PMID:Increased microvascular permeability in vivo in response to intradermal injection of neutrophil-activating protein (NAP-2) in rabbit skin. 182 7

Isolation of the human neutrophil activating protein (NAP) interleukin 8 (IL8) from leukocytes has revealed that it is structurally related to beta-thromboglobulin (beta TG) from platelets. Both these proteins occur as natural mixtures of multiple forms, differing from each other by unequal truncation at the NH2 terminus. In this study we have compared IL8 and beta TG forms for in vitro and in vivo neutrophil activation. In contrast to IL8, none of the beta TG forms were found to exert granulocyte chemotactic activity in vitro, as measured in the agarose assay. However, fractions rich in the most extensively processed forms of beta TG (e.g. NAP-2) as well as pure NAP-2 did induce lactoferrin release from granulocytes, whereas fractions containing only the longer forms (e.g. connective tissue-activating peptide III) were inactive. In order to observe this in vitro effect, about 10-fold less IL8 (10 nM) than NAP-2 was required. In the presence of a vasodilator substance low doses (2-20 pmol) of IL8 and the shorter forms of beta TG caused granulocyte accumulation and plasma leakage in rabbit skin whereas the longer forms of beta TG again failed to do so. Finally, granulocytosis induction following i.v. injection was found to occur with NAP-2. At the maximal dose tested (250 pmol), this in vivo effect of NAP-2 was less pronounced than that of IL8. In the case of IL8, NH2-terminal processing did not seem to affect granulocyte stimulatory activity. It should be noted, however, that the extent of processing of IL8 is less than that occurring with beta TG. It can be concluded that the platelet factor beta TG, structurally related to the monokine IL8, can also play a role in neutrophil activation during inflammatory reactions.
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PMID:The neutrophil-activating proteins interleukin 8 and beta-thromboglobulin: in vitro and in vivo comparison of NH2-terminally processed forms. 214 75

Purification of monocyte-derived NAP-1/IL-8 by preparative reversed-phase (RP)-HPLC led to the detection of a second peak with polymorphonuclear leukocyte (PMNL)-activating (degranulation, chemotaxis) properties. The monokine responsible for this biological activity, which we tentatively termed NAP-3, could be purified to homogeneity by three different RP-HPLC steps. Tricine-SDS-PAGE analysis gave a single line at Mr 5.3 kD (NAP-1/IL-8 = 5.8 kD). NH2-terminal amino acid sequence analysis read as a major sequence (ASVATELRXCXLQT. .), which shows greater than 40% homology to that of NAP-1/IL-8. The sequence is identical to that found for the 13-kD moiety of melanoma growth stimulating activity (MGSA) and the product of the oncogene gro. Determination of neutrophil chemotactic activity of NAP-3 revealed a typical bell-shaped dose-response curve (ED50 = 2 ng/ml) with no significant neutrophil chemotactic activity at doses greater than 200 ng/ml. Also, in cytochalasin B-pretreated PMNL, NAP-3 elicited release of myeloperoxidase and beta-glucuronidase. Crossdesensitization studies in PMNL enzyme release revealed crossreactivities with the NAP-1/IL-8-R on PMNL. NAP-3 (MGSA/gro) appears to represent the first member of the novel supergene family of beta-thromboglobulin-like host defense cytokines, which expresses both mitogenic as well as proinflammatory properties at the nanogram level.
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PMID:Lipopolysaccharide-stimulated human monocytes secrete, apart from neutrophil-activating peptide 1/interleukin 8, a second neutrophil-activating protein. NH2-terminal amino acid sequence identity with melanoma growth stimulatory activity. 218 61

Microheterogeneity of connective tissue activation peptide III (CTAP-III) was revealed by preparative and analytical isoelectric focusing. Proteolytic activities in human platelet preparations resulted in four cleavage products of platelet-derived CTAP-III. Three isoforms (CTAP-III des 1-13, des 1-14, and des 1-15/NAP-2) stimulate [14C]glycosaminoglycan synthesis; two isoforms also promote [3H]DNA synthesis in human fibroblast cultures. Elastase (from porcine pancreas) cleavage of human platelet-derived CTAP-III and rCTAP-III-Leu-21 to the des 1-15 isoforms was associated with either preservation of specific anabolic biologic activity or an actual increase in specific activity. Nonenzymatic glycosylation of lysyl residues and deamination of the NH2-terminal asparagine of platelet-derived CTAP-III were commonly present, but did not correlate with the biologic activities that were measured. Protein sequence homology shows CTAP-III and its isoforms to be members of a family of proteins (including NAP-1/II-8, MGSA, and platelet factor-4) known to be associated with growth, wound repair, inflammation, and neoplasia. The consequences of proteolytic processing reported here for CTAP-III may be characteristic of the other proteins in this group.
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PMID:Connective tissue activation. XXXIV: Effects of proteolytic processing on the biologic activities of CTAP-III. 221 61


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