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 novel protein, NAP-4, could be isolated from human platelet lysates. NAP-4 preparations induced chemotaxis of human neutrophils with an ED50 near 400 ng/ml. Purification by anti NAP-1/IL-8 affinity chromatography and reversed phase HPLC revealed a single peak showing a single line upon SDS-PAGE corresponding to a Mr of 8000. NH2-terminal sequence analysis indicated an unique sequence showing strong homology to human platelet factor 4 and weak homology to tumor necrosis factor alpha as well. The most interesting finding is the absence of the first two cysteins, known to be strongly conserved in members of the family of platelet-factor 4-like host defense cytokines.
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PMID:Identification of a novel platelet-derived neutrophil-chemotactic polypeptide with structural homology to platelet-factor 4. 224 78

Previously we have isolated about 60 novel cDNA clones whose corresponding mRNAs are induced by mitogenic activation in human peripheral blood T cells. Here we describe the primary structure and regulation of two such cloned genes, pAT 464 and pAT 744, which may encode new lymphokines/cytokines. Similar to IL-2, both genes require the synergy of agents such as PHA and PMA for optimal expression, and, in addition, the induction of both is sensitive to the immunosuppressive drug cyclosporin A. The two genes can be expressed in T cells, B cells, and the promyelocytic cell line HL60, but they are not expressed in human fibroblasts, suggesting that their expression is restricted to hematopoietic lineages. The predicted peptides encoded by these two clones feature hydrophobic N-terminal leaders characteristic of secreted proteins. The predicted size of both proteins is about 8 kDa upon cleavage of the putative leader peptide. pAT 464 and pAT 744 are very similar to each other and also share some critical amino acid similarity with a newly emerging family of secreted factors including connective tissue activating factor III, platelet factor 4, an IFN-gamma-induced factor, macrophage inflammatory protein, and a factor chemotactic to neutrophils (3-10C, monocyte-derived neutrophil chemotactic factor, neutrophil-activating factor). Some of these factors have been shown to display functions associated with an inflammatory response and/or have mitogenic activities. Collectively, the data presented here suggest that pAT 464 and pAT 744 encode novel lymphokines/cytokines which may play roles during an immune response similar to those enacted by these structurally related factors.
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PMID:Mitogenic activation of human T cells induces two closely related genes which share structural similarities with a new family of secreted factors. 252 82

LPS-stimulated human mononuclear cells have recently been shown to produce large amounts of a novel neutrophil-activating cytokine termed neutrophil-activating peptide NAP/IL-8. This chemotactic factor has in the meantime been biochemically and functionally well characterized. We now report on four distinct murine mAb directed against this peptide. All four mAb are different in respect to isotype and IEF pattern. The cross-reactivity with partially homologous peptides like beta-thromboglobulin and platelet factor 4 showed defined differences. With the use of these antibodies we were able to detect solid phase as well as soluble NAP/IL-8 as tested in a sandwich-ELISA. Also dose-dependent neutralization of NAP/IL-8 chemotactic activity in the Boyden chamber chemotaxis assay was observed. Immunoaffinity columns prepared with these four mAb bound NAP/IL-8 from supernatants of LPS-stimulated mononuclear cells. Furthermore, Western immunoblots showed a single protein band in the expected region of Mr of 10 kDa with all four mAb presented.
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PMID:Production and characterization of monoclonal antibodies against the novel neutrophil activating peptide NAP/IL-8. 266 11

Platelet basic protein (PBP), connective tissue-activating peptide III (CTAP-III), and platelet factor 4 (PF-4) were purified from human platelet release supernatants by heparin-Sepharose ion-exchange and reversed-phase HPLC, and their neutrophil-activating effects were compared with those of NAP-2, a peptide of 70 amino acids corresponding to part of the sequence of PBP (1) and with sequence homology to NAF/NAP-1. NAP-2-induced elastase release and a rise in cytosolic free Ca2+ at concentrations between 0.3 and 100 nM, and neutrophil chemotaxis at concentrations between 0.03 and 10 nM. It was half as potent as NAF/NAP-1 in inducing exocytosis but showed the same activity in the other responses. By contrast, only minimal if any effects were obtained with PBP, CTAP-III, and PF-4 up to 100 nM. NAP-2 thus appears to behave like a typical chemotactic receptor agonist. It could be generated from PBP and/or CTAP-III released from activated platelets and lead to the accumulation of neutrophils in platelet aggregates.
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PMID:Effects of the neutrophil-activating peptide NAP-2, platelet basic protein, connective tissue-activating peptide III and platelet factor 4 on human neutrophils. 268 18

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

A factor able to induce an early local inflammation in rabbit skin was detected in the supernatant of mitogen-stimulated human blood leukocytes. The factor was different from IL-1 which, although present in the supernatants, was chemically separable from the factor and induced a late rather than an early skin response. Other biological effects of the principal factor were its in vitro chemotactic effects on granulocytes and its ability to induce rapid granulocytosis upon intravenous injection in rabbits. When tested under the same conditions, IL-1 beta did not act chemotactically and induced granulocytosis at a later time. The factor was purified to homogeneity and identified by electrophoretic mobility as a protein of Mr 6,500. Amino acid sequence analysis revealed the presence of an uncontaminated NH2-terminal sequence identical to a segment of the sequence previously predicted from the cDNA clone (3-10C) copied from an mRNA isolated from human leukocytes and coding for a protein of unknown function. The NH2-terminal sequence of the factor also showed extensive homology to that of the platelet factors beta-thromboglobulin (beta TG) and platelet factor 4 (PF-4). Studies done to identify the cell source of the factor revealed that it was produced by adherent mononuclear cells but not by platelets, while the opposite was true for beta TG.
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PMID:A novel, NH2-terminal sequence-characterized human monokine possessing neutrophil chemotactic, skin-reactive, and granulocytosis-promoting activity. 325 25

Stimulatory cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF) and steel factor (SLF), act in a synergistic manner to stimulate the growth of hematopoietic progenitor cells, an effect also demonstrated for the growth factor-dependent human hematopoietic cell line MO7e. While little is known about the mechanisms responsible for mediating synergistic interactions of cytokines, Raf-1, a component of the MAP kinase signaling pathway, is thought to play a role in the stimulatory response evoked by several cytokines, including SLF and GM-CSF. Interferon-inducible protein-10 (IP-10) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) are members of the chemokine family of suppressive cytokines. Prior exposure of hematopoietic cells to chemokines, including IP-10 and MIP-1 alpha, inhibits the synergistic action of growth factors on stimulating cell proliferation. We report that treatment of MO7e cells with the combination of GM-CSF and SLF directly stimulates statistically significant synergistic increases in the phosphorylation and activation of Raf-1 kinase, and in cellular protein synthesis levels. Pretreatment of MO7e cells with IP-10 or MIP-1 alpha blocked synergistic growth factor action, resulting in statistically significant suppression of cell proliferation, protein synthesis, and Raf-1 phosphorylation and activation. IP-10 and MIP-1 alpha treatment also evoked significant increases in intracellular cAMP levels. Pretreatment of cells with agents which serve to raise intracellular cAMP levels, or with cAMP analogs inhibited the synergistic actions of GM-CSF and SLF in a manner similar to IP-10 and MIP-1 alpha. In addition, treatment of cells with a potent inhibitor of cAMP-dependent protein kinase A blocked the suppressive action of MIP-1 alpha and IP-10 on Raf-1 kinase activity and on MO7e cell proliferation. The ability of IP-10 and MIP-1 alpha to antagonize the synergistic action of GM-CSF and SLF appears to involve inactivation of Raf-1 and the down-regulation of protein synthesis. Our findings suggest that both MIP-1 alpha and IP-10 mediate their suppressive effects in MO7e cells by stimulating increases in cellular cAMP levels and activating protein kinase A, a mechanism we believe to be unique to these chemokines and not one applied to all growth suppressive members of the chemokine superfamily (for example, interleukin 8 and platelet factor 4).
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PMID:Interferon-inducible protein 10 and macrophage inflammatory protein-1 alpha inhibit growth factor stimulation of Raf-1 kinase activity and protein synthesis in a human growth factor-dependent hematopoietic cell line. 1660 26

The proliferation of human myeloid progenitor cells is negatively regulated in the presence of certain members of the chemokine family of molecules. This includes interleukin 8 (IL-8) and platelet factor 4 (PF4), which in combination are able to synergize, resulting in cell suppression at very low concentrations of these molecules. A series of PF4 and IL-8 mutant proteins were analyzed in an in vitro colony formation assay for myeloid progenitor cells to assess domains of these proteins that are required for activity. Mutation of either of the two DLQ motifs within PF4 resulted in an inactive protein. Perturbations within the IL-8 dimer interface region also resulted in mutants that were incapable of suppressing colony formation. A class of chimeric mutants consisting of domains of either PF4 and IL-8, Gro-alpha and PF4, or Gro-beta and PF4 were observed to inhibit myeloid cell proliferation at concentrations which were between 500- and 5000-fold lower than either the IL-8 or PF4 wild-type proteins alone. These chimeric mutants possessed activities that were comparable to or better than the activity observed when IL-8 and PF4 were added together in vitro. One of these highly active chimeric proteins was observed to be 1000-fold more active than either IL-8 or PF4 alone in suppressing not only the proliferation but also the cell cycling of myeloid progenitor cells following intravenous injection of the mutant into mice. Examination of additional IL-8-based mutants in the colony formation assay, which centered on the perturbation of the amino-terminal "ELR" motif, resulted in the observation that the highly active IL-8 mutant required both aspartic acid at amino acid residue 4 and either glutamine or asparagine at residue 6. Single mutations at either of these positions resulted in mutants with myelosuppressive activity equivalent to wild-type IL-8. Mutants such as IL-8M1 and IL-8M10 were observed to be significantly reduced in their ability to activate isolated human neutrophils, suggesting that separate mechanisms may exist by which myeloid progenitor cells and neutrophils are affected by chemokines.
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PMID:High activity suppression of myeloid progenitor proliferation by chimeric mutants of interleukin 8 and platelet factor 4. 755 82

We have previously shown that platelet factor 4 (PF4), a platelet-specific CXC chemokine, can directly and specifically inhibit human megakaryocyte colony formation. We therefore hypothesized that PF4 might function as a negative autocrine regulator of megakaryocytopoiesis. Herein we present additional studies characterizing the inhibitory effect of CXC chemokines on human megakaryocyte development. We first corroborated our initial studies by showing that recombinant human (rH) PF4, like the native protein, inhibited megakaryocytopoiesis. We then examined the inhibitory properties of other CXC family members. Neutrophil activating peptide-2 (NAP-2), a naturally occurring N-terminally cleaved beta TG peptide, was found to inhibit megakaryocytopoiesis with two to three orders of magnitude greater potency than PF4. Structure function studies showed that an N-terminal mutation, which eliminated NAP-2's neutrophil activating properties (NAP-2E2-->A), also abrogated its ability to inhibit megakaryocyte development. Further investigations of this type demonstrated that a chimeric PF4 protein (AELR/PF4) in which PF4's N-terminus was replaced with the first four amino acids of NAP-2 was also a potent inhibitor of megakaryocytopoiesis. Interleukin (IL)-8, another CXC chemokine, and three CC chemokines (macrophage inhibitory protein-1 alpha [MIP-1 alpha], MIP-1 beta, and C10) also specifically inhibited megakaryocyte colony formation at NAP-2 equivalent doses. CXC and CC chemokine inhibition was additive suggesting that the effects might be mediated through a common pathway. The inhibitory effects of NAP-2 and MIP-1 alpha could not be overcome by adding physiologically relevant amounts of recombinant human megakaryocyte growth and development factor (MGDR) (50 ng/mL) to the cultures. Using Northern blot and reverse transcriptase-polymerase chain reaction (RT-PCR) based analyses, we documented mRNA expression of IL-8 receptor isoforms alpha and beta in total platelet RNA and in normal human megakaryocytes, respectively. Based on these results, we hypothesize that chemokines play a physiologic role in regulating megakaryocytopoiesis. Because chemokines are elaborated by ancillary marrow cells, both autocrine and paracrine growth control is suggested, the effects of which might be exerted, in part, through alpha and beta IL-8 receptors.
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PMID:Chemokine regulation of human megakaryocytopoiesis. 767 Jan 1

Macrophage inflammatory protein (MIP)-1 alpha, part of a family termed chemokines, has been implicated in suppression of hemopoietic stem and progenitor cell proliferation. The chemokine family has been organized into two subgroups with MIP-1 alpha, MIP-1 beta, macrophage chemotactic and activating factor (MCAF) and RANTES belonging to one subgroup, and GRO-alpha, MIP-2 alpha (GRO-beta), MIP-2 beta (GRO-gamma), platelet factor 4 (PF4), IL-8, and neutrophil activating peptide (NAP)-2 belonging to the other. These molecules were evaluated for effects on colony formation by human bone marrow multipotential (CFU-GEMM), erythroid (BFU-E) and granulocyte-macrophage (CFU-GM) progenitor cells. None of the chemokines stimulated colony formation in the absence of CSF, or influenced colony formation stimulated by a single growth factor such as granulocyte-macrophage-CSF or erythropoietin. However, MIP-1 alpha, MIP-2 alpha, PF4, IL-8, and MCAF suppressed in dose-response fashion colony formation of immature subsets of myeloid progenitor cells stimulated by GM-CSF plus steel factor. Effects were apparent on low density and CD34 HLA-DR(+)-sorted marrow cells in which up to 88.4% of the cells were composed of progenitor cells, suggesting direct effects on the progenitors themselves. Up to 2500-fold less of each chemokine could be used to demonstrate synergistic suppression when any two of these five chemokines were used together at low concentrations, effects also apparently directly on the progenitors. In contrast, MIP-1 beta, MIP-2 beta, GRO-alpha, NAP-2, and RANTES were not suppressive nor did they synergize with MIP-1 alpha, MIP-2 alpha, PF4, IL-8, or MCAF to suppress. However, a fivefold excess of MIP-1 beta blocked the suppressive effects of MIP-1 alpha. Similarly, a fivefold excess of either MIP-2 beta or GRO-alpha blocked the suppressive effects of IL-8 and PF4. These suppressing, synergizing and blocking effects may be of relevance to blood cell regulation.
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PMID:Comparative analysis of the human macrophage inflammatory protein family of cytokines (chemokines) on proliferation of human myeloid progenitor cells. Interacting effects involving suppression, synergistic suppression, and blocking of suppression. 768 42


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