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)

According to the type of secondary structure, cytokines are classified into three categories: alpha-spiral (IFNs-alpha, beta, omega, gamma; ILS-2, 3,4,5,6,7,9; CSFs-G, M, GM, MGF, PDGF), beta-structural (ILs-1 alpha, beta, TNFs-alpha, beta, FGF) and (alpha + beta)-structural proteins (IL-8, IFN-gamma IP-10, PF-4, bTG, GRO, 9E3). According to the type of tertiary structure, alpha-spiral proteins are grouped into IFN- and IL-2-like families and beta-structural ones into IL-1-, and TNF-like families. Two subfamilies can be identified in the IFN-like family. Theoretical and experimental evidence suggests that the genes IFNs are products of divergent or convergent evolution towards the gene of the ancient intracellular protein alpha-prothymosine, which is evolutionally in turn associated with the L7/I1 protein of two ribosomes. It is suggested that the proteins of the immunoglobulin superfamily, including cytokine receptors descended from the ancient proteins of the unicellular organisms molecular shaperons.
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PMID:[The structural and functional classification and evolution of cytokines]. 768 23

IP-10 is a member of the chemokine family of cytokines and is induced in a variety of cells in response to interferon gamma and lipopolysaccharide. The self-aggregation common to many chemokines, including IP-10, has hindered the identification of a specific IP-10 receptor. Using an IP-10 alkaline phosphatase fusion protein that fortuitously blocks this self-aggregation, we have identified an IP-10 binding site on a variety of cells including endothelial, epithelial, and hematopoietic cells. This binding site has a Kd of 25 nM, is inhibited by recombinant murine or human IP-10, and is dependent on the presence of cell surface heparan sulfate proteoglycans (HSPG). This conclusion is based on the findings that IP-10 binding to cells is: (a) inhibited by heparin and heparan sulfate; (b) sensitive to a 1 M NaCl wash; (c) eliminated by treatment with heparinase and trypsin; and (d) absent on mutant CHO cells that do not express cell surface HSPG. Platelet factor 4 (PF4), but not IL-8, monocyte chemoattractant protein-1, RANTES, monocyte inflammatory protein (MIP)-1 alpha, or MIP-1 beta, can compete effectively with IP-10 for binding to the cell surface. Furthermore, IP-10 shares with PF4 the ability to inhibit endothelial cell proliferation (IC50 = 150 nM). These studies demonstrate specificity in the interaction of chemokines and HSPG, and they define IP-10 and PF4 as a distinct subset of chemokines sharing an HSPG-binding site and angiostatic properties.
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PMID:The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation. 779 Aug 18

The responses of lymphocytes to six CC chemokines--MCP-1, MCP-2, MCP-3, MIP-1 alpha, MIP-1 beta, and RANTES--were studied using cloned human CD4+ and CD8+ T cells. All CC chemokines tested induced migration of both types of lymphocytes, whereas two CXC chemokines used as controls, IL-8 and IP-10, were inactive. The monocyte chemotactic proteins (MCP-1, MCP-2, and MCP-3) showed a typically bimodal concentration dependence, and were considerably more effective than MIP-1 alpha, MIP-1 beta, or RANTES. All CC chemokines also induced a rapid and transient rise in cytosolic free Ca2+ in either type of T cell. The rise was prevented by Bordetella pertussis toxin treatment, indicating that G-protein-coupled receptors are involved in signaling. It was most pronounced with MCP-1 and MCP-3, which is in agreement with the efficacy of these chemokines as chemoattractants. The responses to MCP-2, MIP-1 alpha, MIP-1 beta, and RANTES were weaker, and no changes were obtained on stimulation with IL-8 or IP-10. Freshly isolated human blood lymphocytes were also tested, but neither migration nor Ca2+ changes were observed. Low numbers of high-affinity receptors for MCP-1 were found on CD4+ and CD8+ cells ( < 900 per cell, Kd < 1 nM), and desensitization experiments showed that MCP-1, MCP-2, and MCP-3 share receptors. Owing to their superior effectiveness on CD4+ and CD8+ T cells, the monocyte chemotactic proteins could play a major role in the recruitment of activated T lymphocytes.
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PMID:Monocyte chemotactic proteins MCP-1, MCP-2, and MCP-3 are major attractants for human CD4+ and CD8+ T lymphocytes. 792 71

Because leukocyte-mediated tissue damage is an important component of the pathologic picture in ischemia/reperfusion, we have sought mechanisms by which PMNs are directed into hypoxic tissue. Incubation of human endothelial cells (ECs) in hypoxia, PO2 approximately 14-18 Torr, led to time-dependent release of IL-8 antigen into the conditioned medium; this was accompanied by increased chemotactic activity for PMNs, blocked by antibody to IL-8. Production of IL-8 by hypoxic ECs occurred concomitantly with both increased levels of IL-8 mRNA, based on polymerase chain reaction analysis, and increased IL-8 transcription, based on nuclear run-on assays. Northern analysis of mRNA from hypoxic ECs also demonstrated increased levels of mRNA for macrophage chemotactic protein-1, another member of the chemokine superfamily of proinflammatory cytokines. IL-8 gene induction was associated with the presence of increased binding activity in nuclear extracts from hypoxic ECs for the NF-kB site. Studies with human umbilical vein segments exposed to hypoxia also demonstrated increased elaboration of IL-8 antigen compared with normoxic controls. In mice exposed to hypoxia (PO2 approximately 30-40 Torr), there was increased pulmonary leukostasis, as evidenced by increased myeloperoxidase activity in tissue homogenates. In parallel, increased levels of transcripts for IP-10, a murine homologue in the chemokine family related to IL-8, were observed in hypoxic lung tissue. Taken together, these data suggest that hypoxia constitutes a stimulus for leukocyte chemotaxis and tissue leukostasis.
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PMID:Hypoxic induction of interleukin-8 gene expression in human endothelial cells. 816 58

Recent studies suggest that cytokines such as recombinant interferon-gamma (rIFN-gamma) may play a role in the treatment of certain respiratory conditions associated with infection and inflammation. This study was designed to determine if rIFN-gamma could be delivered effectively in a group of normal human volunteers. The effectiveness of the inhaled delivery system was demonstrated by the recovery of free IFN-gamma in bronchoalveolar lavage (BAL) fluid and macrophage (M phi) expression of IP-10, an IFN-gamma-inducible molecule, after therapy but not at baseline. IL-1 beta, but not IL-8, gene transcripts also showed evidence for up-regulation after rIFN-gamma therapy. Compared with baseline, inhaled rIFN-gamma did not significantly alter clinical symptom scores, spirometry, morning peak expiratory flow rate (PEFR), or the response to methacholine. Of interest, the evening PEFR increased significantly (p = 0.02), from 568 +/- 36 L/min at baseline to 584 +/- 33 L/min after inhaled rIFN-gamma. Although there was no significant change in total white cell count in BAL fluid, the cellular composition did demonstrate a significant decrease in percentage of alveolar M phi (p = 0.02) and an increase in percentage of lymphocytes (p = 0.02) after rIFN-gamma. There were no histologic differences seen in bronchial biopsy specimens, and there was no evidence for up-regulation of ICAM-1 or HLA-DR expression after rIFN-gamma. We conclude that, in normal persons, rIFN-gamma can be effectively delivered by inhalation. Future trials using inhaled rIFN-gamma appear to be warranted for certain pulmonary diseases.
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PMID:The effects of inhaled interferon gamma in normal human airways. 825 19

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

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.
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PMID: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. 842 27

In response to interleukin 1 or tumor necrosis factor, human synovial cells and fibroblasts expressed several genes encoding known chemotactic factors or related proteins. Transcripts for interleukin 8 (IL-8), gro/MGSA, pAT 464, IP-10, pAT 744 and Monocyte Chemotactic and Activating Factor (MCAF) accumulated rapidly in IL-1 and TNF-treated cells. The inhibition of protein synthesis led to the superinduction of IL-8 and gro/MGSA mRNAs in IL-1, but not in TNF-treated cells. Thus, IL-1 and TNF are likely to regulate the expression of these mRNAs by different mechanisms. Important cell-specific differences in mRNA accumulation characterized the expression of chemotactic factor genes. Moreover, only a subset of the same genes was activated in quiescent cells stimulated by serum. Therefore, genes encoding closely related proteins each had a distinct pattern of expression. continuous stimulation of fibroblasts and synovial cells with IL-1 resulted in high and prolonged expression of IL-8 and gro/MGSA mRNAs. These results extend the list of chemotactic factor genes expressed by mesenchymal cells in vitro and suggest a pivotal role for these cells in processes such as chronic inflammation.
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PMID:Cytokine-induced expression of mRNAs for chemotactic factors in human synovial cells and fibroblasts. 842 22

The initiation and promulgation of chronic inflammation are controlled in part by the various pro-inflammatory and anti-inflammatory cytokines present at the site of injury. IFN-gamma and granulocyte-macrophage CSF (GM-CSF) are two cytokines that can contribute to the inflammatory state and possess both pro- and anti-inflammatory properties. However, the characterization of the interaction between GM-CSF-cultured monocytes and IFN-gamma is poorly documented. In this report we show that culture of human peripheral blood monocytes for up to 6 days in the presence of GM-CSF results in an eightfold increase in the level of IFN-gamma R expression, as determined by radioligand binding. The IFN-gamma R on these cells maintains a specificity typical of that observed in fresh monocytes. Only IFN-gamma, not IFN-alpha or -beta, blocks the binding of IFN-gamma to its receptor, and anti-IFN-gamma R antibodies block at least 80% of binding of IFN-gamma to these cultured cells. However, in spite of increased receptor expression, GM-CSF-cultured monocytes have a diminished response to IFN-gamma, as measured by the induction of the gene for IP-10 (a member of the platelet factor-4/IL-8 family). On the other hand, IFN-gamma-induced activation of the DNA-binding protein FcRF gamma is maintained in GM-CSF-cultured monocytes. Therefore, suppression of IFN-gamma-mediated IP-10 induction is not the result of a global abrogation of signal transduction across the IFN-gamma R but a more selective inhibition that appears to occur downstream of the receptor.
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PMID:Culture of human monocytes with granulocyte-macrophage colony-stimulating factor results in enhancement of IFN-gamma receptors but suppression of IFN-gamma-induced expression of the gene IP-10. 845 Feb 19

The responses of cloned human NK cells (ERNK57) to seven CC chemokines (monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3, RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein-1 alpha (MIP-1 alpha), MIP-1 beta, and 1309) and two CXC chemokines (IL-8 and IP-10) were studied. Except for 1309, all CC chemokines induced chemotaxis of the NK cells in vitro, whereas the CXC chemokines were inactive. Maximal activity was obtained at 1 nM for MCP-1 and 10 to 100 nM for the other CC chemokines. The response showed a typically bimodal concentration dependence in all cases, except for RANTES, which induced a linear increase of migration over the concentration range of 0.1 to 1000 nM. A transient rise of the cytosolic-free Ca2+ concentration ([Ca2+]i), which is characteristic for chemokine-stimulated leukocytes, was observed in NK cells after stimulation with all six active chemokines. Since granule exocytosis is required for NK cell-dependent target killing, the effect of CC chemokines on exocytosis was tested. All CC chemokines that induced chemotaxis and [Ca2+]i changes also induced the release of granzyme A and N-acetyl-beta-D-glucosaminidase from cloned and blood NK cells, as well as CD8+ T cells after pretreatment with cytochalasin B. Maximum release was obtained from NK cells, and amounted to 35% and 13% of the total content of granzyme A and N-acetyl-beta-D-glucosaminidase, respectively. The capacity of cloned NK cells and CD8+ T cells to respond to chemokines depended on the time in culture after stimulation with PHA in the presence of irradiated feeder cells, and maximum responses were observed after 10 to 16 days. Our results demonstrate that CC chemokines activate NK cells, and are, therefore, not only attractants for monocytes, T lymphocytes, and eosinophil and basophil granulocytes.
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PMID:Activation of NK cells by CC chemokines. Chemotaxis, Ca2+ mobilization, and enzyme release. 859 80


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