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)

Recombinant human monocyte-derived interleukin-8 (IL-8M), recombinant human endothelium-derived IL-8 (IL-8E), and a recombinant human truncated form of IL-8 (IL-8T) stimulated a time-dependent (t 1/2 approximately 2-3 s) and concentration-dependent (0.1-100 nM) release of azurophil (myeloperoxidase) and specific (vitamin B12 binding protein, gelatinase) granule constituents from cytochalasin B-treated human neutrophils (HNs) wherein IL-8T = IL-8M greater than IL-8E. An increase in the cytosolic free calcium concentration ([Ca2+]i) was greater in IL-8T- than in IL-8M- or IL-8E-activated HNs, and IL-8T was more potent than either IL-8M or IL-8E in sequentially desensitizing the HNs to the effects of the other IL-8 forms. IL-8 induced a time- and concentration-dependent (0.1-100 nM) increase in the production of inositol 1,4,5-trisphosphate (IP3) in HNs. U-73122 (1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17- yl]amino]hexyl]-1H-pyrrole-2,5-dione), a potent inhibitor of phospholipase C-catalyzed events in HNs, suppressed IL-8-triggered IP3 production, increased [Ca2+]i and granule exocytosis in HNs. The membrane-associated activity of the alpha and beta subtypes of protein kinase C was significantly enhanced in IL-8-activated cells.
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PMID:Postreceptor events associated with human neutrophil activation by interleukin-8. 132 42

Phorbol ester (TPA) and retinoic acid (RA) are two potent immunomodulatory agents whose actions are mediated through distinct signal transduction pathways involving protein kinase C (PKC) and nuclear RA receptors, respectively. We have investigated the interactions between these two pathways in the regulation of expression of the inflammatory cytokine IL-8 in human skin fibroblasts. TPA (as previously reported) and RA both induced IL-8 mRNA and protein in a time- and dose-dependent manner. IL-8 mRNA induction by TPA (10 nM) was maximal (15-fold) within 6 h, and returned to baseline within 24 h of treatment, although maximal induction (10-fold) by RA (1 microM) did not occur until 24 h posttreatment. Induction of IL-8 by TPA was blocked by 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine, which inhibits PKC and cAMP-dependent protein kinases (PKA), but not by N-(2-ganidinoethyl)-5-isoquinoline sulfonamide, which preferentially inhibits PKA, consistent with the participation of PKC in the induction of IL-8 by TPA. In contrast, induction of IL-8 by RA was inhibited by both 1-(5-isoquinoline sulfonamide and N-(2-gamidinoethyl)-5-isoquinoline sulfonamide, suggesting the participation of PKA in the induction of IL-8 by RA. However, activation of PKA by addition of cAMP analogues was not sufficient to induce IL-8 expression. Induction of IL-8 by RA also did not appear to be mediated indirectly through induction of IL-1, because addition of IL-1R antagonist did not block IL-8 induction by RA. RA and TPA added in combination synergistically enhanced expression of IL-8 mRNA, measured at 6 (2-fold) and 24 h (10-fold) posttreatment. To investigate the mechanism of this synergy, the effect of TPA and RA on fibroblast PKC activation and PKC isozyme levels were determined. TPA, either alone or together with RA, but not RA alone, stimulated phosphorylation of an endogenous 80-kDa PKC substrate. Dermal fibroblasts expressed three PKC isozymes (alpha, (delta, and (epsilon). TPA, but not RA, down-regulated PKC-alpha, neither TPA or RA affected the level of PKC-delta, and both TPA and RA down-regulated PKC-epsilon. This latter effect was enhanced 2-fold by addition of RA and TPA together. These data suggest that modulation of PKC-epsilon may be a common participant in the regulation of IL-8 expression by TPA and RA.
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PMID:Retinoic acid and phorbol ester synergistically up-regulate IL-8 expression and specifically modulate protein kinase C-epsilon in human skin fibroblasts. 132 13

Recent cloning of human and murine IL-1 receptor (IL-1R) has revealed that there are at least two type of IL-1R: type I IL-1R is detected on T cells and fibroblasts and consists of 552 AAs with a cytoplasmic domain of 213 AAs, while type II is detected on B cells and monocytic cell lines and consists of 398 AAs with a short stretch intracytoplasmic domain of 29 AAs. Extracytoplasmic portion of IL-1R has some homology with vaccinia virus B15 Ag or fibroblast protein ST-2, while cytoplasmic portion has considerable similarity with Drosophila toll gene. By transfecting murine type I IL-1R cDNA into a human Jurkat cell line, structural and functional potion required for the IL-1 signal transduction is determined. At least broad portion of cytoplasmic domain including 364-474 AAs from N-terminus are found to be essential, while PKC acceptor site (Ser-431 and Ser-509), and PKA acceptor site (Ser-528) are not essential for the IL-8 gene expression.
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PMID:[Function, molecular structure and gene expression of interleukin-1]. 143 66

Interleukin-8 (IL-8/NAP-1), the neutrophil-activating peptide 2 (NAP-2), and formyl-peptides (fMLP) have been described as potent stimulators for human neutrophils (PMN). We have compared the mechanism of signal transduction induced by these factors during neutrophil activation (elastase release), by using activators and inhibitors and by direct measurement of the enzymatic activity of kinases. Moreover, costimulation kinetics of the combined factors were analyzed. Our results show that each of these stimulators induces elevated levels of cAMP, indicating the activation of adenylate-cyclase. Further results obtained with the kinase inhibitor H-7 and the cAMP analogue dibutyryl-cAMP (dbcAMP) gave evidence that cAMP-dependent kinases are involved in the down-regulation of the activation process. Degranulation could not be prevented by the inhibitor W-7, nor did the treatment of cells with calcium ionophore (A23187) lead to elevation of intracellular calcium levels. Both phenomena exclude the participation of calcium calmodulin-dependent kinases. Further results obtained with the novel protein kinase C (PKC) inhibitor BM 41440 as well as by direct measurement of PKC enzyme activity demonstrated the involvement of PKC in fMLP-mediated stimulation but not with IL-8/NAP-1 or NAP-2. Analysis of costimulation experiments conducted with these three factors and TPA confirmed these results and gave evidence that fMLP activates two different signaling pathways, one of which is PKC dependent, while the other is not. Moreover, our data indicate that NAP-2, IL-8/NAP-1, and fMLP use identical PKC-independent transduction mechanisms.
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PMID:Neutrophil-activating polypeptides IL-8 and NAP-2 induce identical signal transduction pathways in the regulation of lysosomal enzyme release. 165 69

IL-8 is produced by a wide variety of cells in response to polyclonal mitogens and cytokines. Northern blotting analysis revealed that IL-1, TNF and PMA could induce rapid expression of IL-8 mRNA in the absence of new protein synthesis. Nuclear run-off assays using different cell types demonstrated that IL-8 mRNA expression could at least be partly due to the activation of transcription. Cloning and determination of the entire sequence of IL-8 genomic DNA enabled us to explore the functional significance of the 5'-flanking enhancer region of the IL-8 gene by employing CAT assays. The results indicated that the region spanning from -94 to -71 bp is minimally sufficient for conferring responsiveness to IL-1, TNF and PMA. Further analysis using point-mutations revealed that this region consisted of two distinct cis-elements; one being the potential binding site for NFkB-like and the other for a C/EBP-like factor. These results suggested that all three stimuli, IL-1/TNF/PMA, modulate the identical combination of nuclear factors possibly by phosphorylation. We previously reported that these three stimuli activated the same serine protein kinase which phosphorylates identical 65 kDa and 74 kDa cytosol proteins in human PBMC. This IL-1/TNF/PMA-activated protein kinase is distinct from protein kinase A, protein kinase C or casein kinase in substrate specificity; in Ca and phospholipid dependency; in cyclic nucleotide dependency; and sensitivity to protein kinase inhibitors. Taken collectively, IL-1/TNF/PMA may activate a common serine protein kinase and this protein kinase may in turn directly or indirectly modulate several nuclear factors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of human interleukin 8 gene expression and binding of several other members of the intercrine family to receptors for interleukin-8. 175 77

Essentially pure preparations of normal density eosinophils obtained from patients with hypereosinophilic syndrome (HES) were stimulated with complement factor 5a (C5a), platelet-activating factor (PAF), FMLP and neutrophil-activating peptide (NAP-1/IL-8). Three responses were studied, the transient rise in cytosolic free calcium concentration ([Ca2+]i) (derived from indo-1 fluorescence), shape changes (measured by laser turbidimetry), and exocytosis of eosinophil peroxidase (EPO) (assessed by H2O2/luminol-dependent chemiluminescence). Responses were obtained with all four agonists, but C5a and PAF were by far more potent than FMLP and NAP-1/IL-8, which induced only minor effects. Pretreatment of the cells with pertussis toxin attenuated [Ca2+]i changes, EPO release and, to a lesser extent, shape changes, indicating that GTP-binding proteins of Gi-type are involved in receptor-dependent signal transduction processes leading to these responses. A clear dissociation was observed in the control of the shape change response and EPO exocytosis. The shape change was not affected by Ca2+ depletion or treatment with the protein kinase inhibitor staurosporine, but exocytosis was prevented by Ca2+ depletion and markedly enhanced by staurosporine. The activation of the contractile system, leading to shape changes and motility, thus appears to be independent of the classical signal transduction pathway involving phospholipase C, a [Ca2+]i rise and protein kinase C activation. Exocytosis is, as expected, Ca2+ dependent and appears to be under a negative control involving protein phosphorylations.
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PMID:Shape changes, exocytosis, and cytosolic free calcium changes in stimulated human eosinophils. 204 Jun 92

To further investigate the intracellular mechanisms involved in IL-8-induced human mixed peripheral blood lymphocyte (PBL) migration, the effects of pertussis toxin (PTX), cholera toxin (CTX), and protein kinase C (pkC) inhibitors were investigated. Potent inhibition of IL-8-induced PBL migration was observed following exposure of PBL to PTX and CTX (1 pM to 0.1 microM), 8-bromo cyclic adenosine monophosphate (cAMP; 1 nM to 1 microM), H7 (1 pM to 0.1 microM), sphingosine (0.1 microM to 100 microM) and the novel pkC inhibitors Ro 31-7549 and Ro 31-8220 (10 pM to 1 microM) for 10 min. Following incubation of the lymphocytes for 30 min in the presence of the direct activators of pkC, 1-oleoyl-2-acetyl-sn-glycerol (OAG) and 1,2-dioctanoyl-sn-glycerol (DOG; 10nM to 100 microM), there was a reversal of the effects of a suboptimal dose of the specific pkC inhibitors Ro 31-7549 and Ro 31-8220. These results suggest that intracellular signals transduced during IL-8-induced in vitro PBL migration may involve pertussis and cholera toxin-sensitive G protein subunits and activation of pkC, processes which are characteristically linked to receptor binding.
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PMID:Interleukin (IL)-8-induced in vitro human lymphocyte migration is inhibited by cholera and pertussis toxins and inhibitors of protein kinase C. 216 26

The rise in cytosolic free Ca2+, shape change, superoxide formation, and granule exocytosis induced in human neutrophils by N-formyl-Met-Leu-Phe (fMLP) and by a newly discovered activating peptide, neutrophil-activating factor, termed NAF, were compared. NAF was effective in the concentration range of 0.1-10 nM and was 10- to 100-fold more potent than fMLP. In qualitative terms, the single responses to either stimulus were remarkably similar: they showed virtually identical onset and initial kinetics, and were all inhibited by pretreatment of the neutrophils with Bordetella pertussis toxin. In addition, the respiratory burst elicited by either stimulus was inhibited by 17-hydroxywortmannin and staurosporine. Two conclusions are drawn from these results: 1) neutrophil activation by NAF (as by fMLP) is dependent on a GTP-binding protein and on protein kinase C; 2) a similar, or even identical, mechanism of signal transduction must be assumed on stimulation of human neutrophils with NAF, fMLP, and other chemotactic agonists. Human monocytes, lymphocytes, and platelets did not show cytosolic free Ca2+ changes when exposed to NAF, which suggests that NAF is selective for the neutrophils.
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PMID:Mechanism of neutrophil activation by NAF, a novel monocyte-derived peptide agonist. 284 Mar 18

The imidazoquinolineamine derivative 1-(2-methyl propyl)-1H-imidazole [4,5-c]quinoline-4-amine (imiquimod) has been shown to induce alpha interferon (IFN-alpha) synthesis both in vivo and in peripheral blood mononuclear cells in vitro. In this study, we show that, in these cells, imiquimod induces expression of several IFNA genes (IFNA1, IFNA2, IFNA5, IFNA6, and IFNA8) as well as the IFNB gene. Imiquimod also induced the expression of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha genes. Expression of all these genes was transient, independent of cellular protein synthesis, and inhibited in the presence of tyrosine kinase and protein kinase C inhibitors. Infection with Sendai virus led to expression of a similar set of cytokine genes and several of the IFNA genes. Imiquimod stimulates binding of several induction-specific nuclear complexes: (i) the NF-kappa B-specific complexes binding to the kappa B enhancer present in the promoters of all cytokine genes, but not in IFNA genes, and (ii) the complex(es) binding to the A4F1 site, 5'-GTAAAGAAAGT-3', conserved in the inducible element of IFNA genes. These results indicate that imiquimod, similar to viral infection, stimulates expression of a large number of cytokine genes, including IFN-alpha/beta, and that the signal transduction pathway induced by both of these stimuli requires tyrosine kinase and protein kinase activity.
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PMID:Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways. 753 79

Human neutrophils are able to kill in vitro colorectal carcinoma cell line SW11-16 coated with mAb 17-1A, but they are not cytotoxic towards a non-immunized tumour target. Neutrophil exposure to the inflammatory cytokine, IL-8, produces a significant increase in antibody-dependent cellular cytotoxicity, which is related to IL-8 concentration. Oxyradical production is one of the lytic mechanisms used by phagocytes, and IL-8 is shown to activate this function, which does not occur if neutrophils are pretreated with the protein kinase C inhibitor, staurosporine, but is increased by R59022, a dyacylglycerol kinase inhibitor. The IL-8 effect is mediated by protein kinase C, which is potentiated by the calcium flux induced by the interaction between antibody coating tumour target and Fc gamma RIII on effector cells, as previously demonstrated. Data suggest a possible new role for IL-8 in tumour surveillance.
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PMID:IL-8 enhances antibody-dependent cellular cytotoxicity in human neutrophils. 759 Aug 96


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