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)

Respiratory syncytial virus (RSV) produces intense pulmonary inflammation, in part, through its ability to induce chemokine synthesis in infected airway epithelial cells. In this study, we compare mechanisms for induction of the CXC chemokine IL-8, in human type II alveolar (A549) cells by RSV infection and by stimulation with the cytokine TNF. Promoter deletion and mutagenesis experiments indicate that although the region from -99 to -54 nt is sufficient for TNF-induced IL-8 transcription, this region alone is not sufficient for RSV-induced IL-8 transcription. Instead, RSV requires participation of a previously unrecognized element, spanning from -162 to -132 nt, that we term the RSV response element (RSVRE), and a previously characterized element at -132 to -99 nt, containing an AP-1 binding site. RSV infection of A549 cells induces increased RSVRE- and AP-1-binding activities and increased synthesis of IFN regulatory factor-1 protein, which is present in the RSVRE-binding complex. These data confirm that the IL-8 gene enhancers are controlled in a stimulus-specific fashion and participation of distinct promoter elements is required to activate gene transcription. These observations are important for rational design of inhibitors of RSV-induced lung inflammation.
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PMID:Requirement of a novel upstream response element in respiratory syncytial virus-induced IL-8 gene expression. 1082 Feb 77

In the present study, we show that Ras activity differentially controls interleukin (IL)-1 induced transcription factor activation by selective regulation of responses mediated by receptor complex components. Initial experiments revealed that stimulation with IL-1 caused a rapid, matrix-dependent activation of Ras. The effect was transient, peaking at 5 min and returning to base levels after 30 min. Activation correlated with pronounced changes in cell shape in EGFPH-Ras transfected cells. Transfection with the dominant negative mutant, Ras(Asn-17), inhibited IL-1 induced activation of the IL-8 promoter as well as of NF-kappa B and AP-1 synthetic promoters in transient transfection assays. Furthermore, overexpression of the IL-1 signaling proteins TRAF6 or MyD88 gave characteristic activation of IL-8, which was accentuated in the presence of IL-1. Co-transfection with Ras(Asn-17) gave a dose-dependent inhibition of TRAF6-induced responses in the presence and absence of IL-1, but had no effect on MyD88 mediated activity. Similarly, induction of NF-kappa B was abolished by Ras(Asn-17) only in TRAF6-transfected cells. In contrast, inhibiting Ras activity limited AP-1-mediated responses through both receptor complex proteins. Constitutively active Ras(Val-12) increased the TRAF6 induced activity of the NF-kappa B pathway similar to the effect induced by IL-1, while the Ras(Val-12) induced activity was not inhibited by co-transfection with a dominant negative TRAF6. Our data show that activation of the Ras GTPase is an early, matrix-dependent response in IL-1 signaling which participates in structural regulation of IL-1-induced genes. In addition, they show that the Ras induced effect selectively regulates TRAF6-mediated activation of the NF-kappa B pathway, suggesting that Ras GTPase represents a convergence point in structural and cytokine responses, with distinct effects on a subset of downstream signaling events.
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PMID:Ras controls tumor necrosis factor receptor-associated factor (TRAF)6-dependent induction of nuclear factor-kappa b. Selective regulation through receptor signaling components. 1108 Apr 97

Peroxisome proliferator-activated (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family. PPARs function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPARalpha is highly expressed in tissues such as liver, muscle, kidney and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPARgamma is predominantly expressed in intestine and adipose tissue. PPARgamma triggers adipocyte differentiation and promotes lipid storage. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPARalpha and PPARgamma, respectively. Furthermore, fatty acids and eicosanoids are natural PPAR ligands: PPARalpha is activated by leukotriene B4, whereas prostaglandin J2 is a PPARgamma ligand. These observations suggested a potential role for PPARs not only in metabolic but also in inflammation control. The first evidence for a role of PPARalpha in inflammation control came from the demonstration that PPARalpha deficient mice display a prolonged response to inflammatory stimuli. It was suggested that PPARalpha deficiency results in a reduced beta-oxidative degradation of these inflammatory fatty acid derivatives. More recently, PPAR activators were shown to inhibit the activation of inflammatory response genes (such as IL-2, IL-6, IL-8, TNFalpha and metalloproteases) by negatively interfering with the NF- kappaB, STAT and AP-1 signalling pathways. PPAR activators exert these anti-inflammatory activities in different immunological and vascular wall cell types such as monocyte/macrophages, endothelial, epithelial and smooth muscle cells in which PPARs are expressed. These recent findings indicate a modulatory role for PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases, such as atherosclerosis and inflammatory bowel disease.
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PMID:Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. 1108

Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) produce IL-6 and IL-8, which contribute to inflammation and joint damage. The promoters of both cytokines possess binding sites for NF-kappaB, C/EBPbeta, and c-Jun, but the contribution of each to the regulation of IL-6 and IL-8 in RA FLS is unknown. We employed adenoviral-mediated gene delivery of a nondegradable IkappaBalpha, or dominant-negative versions of C/EBPbeta or c-Jun, to determine the contribution of each transcription factor to IL-6 and IL-8 expression. Inhibition of NF-kappaB activation significantly reduced the spontaneous and IL-1beta-induced secretion of IL-6 and IL-8 by RA FLS and the IL-1ss-induced production of IL-6 and IL-8 by human dermal fibroblasts. Inhibition of C/EBPbeta modestly reduced constitutive and IL-1beta-induced IL-6 by RA FLS, but not by human dermal fibroblasts, and had no effect on IL-8. Inhibition of c-Jun/AP-1 had no effect on the production of either IL-6 or IL-8. Employing gel shift assays, NF-kappaB, C/EBPbeta, and c-Jun were constitutively activated in RA FLS, but only NF-kappaB and c-Jun activity increased after IL-1beta. The reduction of cytokines by IkappaBalpha was mediated through inhibition of NF-kappaB activation, which resulted in decreased IL-6 and IL-8 mRNA. NF-kappaB was essential for IL-6 expression, because fibroblasts in which both NF-kappaB p50/p65 genes were deleted failed to express IL-6 in response to IL-1. These findings document the importance of NF-kappaB for the regulation of the constitutive and IL-1beta-stimulated expression of IL-6 and IL-8 by RA FLS and support the role of inhibition of NF-kappaB as a therapeutic goal in RA.
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PMID:Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: the dominant role for NF-kappa B but not C/EBP beta or c-Jun. 1112 Aug 52

Interleukin-8 (IL-8), a CXC chemokine, has a central role in leukocyte recruitment to areas of granuloma formation in tuberculosis. In the present studies, we investigated the effect of the T(H)2-derived cytokines IL-4, IL-10, and IL-13 on Mycobacterium tuberculosis-induced IL-8 secretion from purified human monocytes. Our results demonstrate that IL-4 and IL-10 have a down-regulatory effect on IL-8 secretion and that this effect is dose dependent. IL-10 has a greater effect than IL-4 on secretion, and autologous IL-10 secreted from M. tuberculosis-infected monocytes also down-regulates IL-8 secretion. The down-regulatory effect is partly a result of reduced IL-8 mRNA accumulation analyzed by reverse transcription-PCR. When combined, 1 microM IL-4 and IL-10 had an additive effect in decreasing IL-8 secretion and transcription; there was no synergy of action. IL-13 did not have any significant effect on IL-8 gene expression or secretion. The inhibitory effect of IL-10 but not of IL-4 is associated with decreased nuclear binding of the key activating transcription factor NF-kappaB. We show for the first time that M. tuberculosis causes up-regulation of nuclear binding of Oct-1 detected by electromobility gel shift assay. However, neither AP-1 nor Oct-1 nuclear binding was altered by IL-4 or IL-10. In summary, this study demonstrates that type 2 responses have an important role in the regulation of M. tuberculosis-induced IL-8 expression but that the mechanisms by which the different cytokines act are distinct.
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PMID:Down-regulation of interleukin-8 secretion from Mycobacterium tuberculosis-infected monocytes by interleukin-4 and -10 but not by interleukin-13. 1125 9

Interleukin-1 (IL-1) is a central regulator of the immune and inflammatory responses by which various inflammatory genes are induced. Although IL-1 signaling is known to involve PI3-kinase, p38 mitogen-activated protein (MAP) kinase and extracellular signal-regulated kinase (ERK), the crosstalk of these kinases on the IL-1-mediated signal transduction is not clear. We used two specific inhibitors, SB203580 which selectively inhibits p38 MAP kinase and LY294002 which inhibits PI3-kinase, respectively, to explore the involvement of these kinases in the IL-1-induced NF-kappa B activation, using a human glioblastoma cell line, T98G. Two kinase inhibitors decreased IL-1-induced IL-8 mRNA and protein levels markedly. IL-1 caused phosphorylation of p38 MAP kinase with concomitant recruitment of PI3-kinase to IL-1 receptor I (IL-1RI) and its activation. In this context, pretreatment of LY294002, but not SB203580, inhibited IL-1-induced NF-kappa B activation significantly. While IL-1 induced-AP-1 activation was moderate, both LY294002 and SB203580 suppressed IL-1-induced AP-1 activation. These observations were prominent particularly in the TRAF6 transfection system, in which overexpression of wild type TRAF6 augmented the IL-1 mediated NF-kappa B and AP-1 activation, while dominant negative TRAF6 construct (delta TRAF6) suppressed these activation. Namely, LY294002 inhibited TRAF6-mediated IL-1-induced NF-kappa B and AP-1 activation markedly, while SB203580 inhibited TRAF6-induced AP-1 activation but not NF-kappa B activation. Above results indicated that both PI3-kinase and p38 MAP kinase are differentially involved in IL-1-induced NF-kappa B and AP-1 activation.
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PMID:Differential involvement of p38 mitogen-activated protein kinase and phosphatidyl inositol 3-kinase in the IL-1-mediated NF-kappa B and AP-1 activation. 1136 42

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPAR alpha is highly expressed in liver, muscle, kidney and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPAR gamma is predominantly expressed in intestine and adipose tissue, where it triggers adipocyte differentiation and promotes lipid storage. Recently, the expression of PPAR alpha and PPAR gamma was also reported in cells of the vascular wall, such as monocyte/macrophages, endothelial and smooth muscle cells. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPAR alpha and PPAR gamma, respectively. Furthermore, fatty acid-derivatives and eicosanoids are natural PPAR ligands: PPAR alpha is activated by leukotriene B4, whereas prostaglandin J2 is a PPAR gamma ligand, as well as some components of oxidized LDL, such as 9- and 13-HODE. These observations suggested a potential role for PPARs not only in metabolic but also in inflammation control and, by consequence, in related diseases such as atherosclerosis. More recently, PPAR activators were shown to inhibit the activation of inflammatory response genes (such as IL-2, IL-6, IL-8, TNF alpha and metalloproteases) by negatively interfering with the NF-kappa B, STAT and AP-1 signalling pathways in cells of the vascular wall. Furthermore, PPARs may also control lipid metabolism in the cells of the atherosclerotic plaque. In addition, different clinical trials (such as the LOCAT, BECAIT and VA-HIT) as well as animal studies indicate that PPAR activators may have anti-atherogenic properties by reducing the progression of atherosclerotic lesions. In this review, we summarize the evidence indicating that PPAR alpha and PPAR gamma directly modulate vessel wall functions, and its consequences in the control of cardiovascular disease.
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PMID:Peroxisome proliferator-activated receptors (PPARs): nuclear receptors with functions in the vascular wall. 1137 25

Hepatitis C virus (HCV), a major cause of liver disease worldwide, is frequently resistant to the antiviral alpha interferon (IFN). The HCV nonstructural 5A (NS5A) protein has been implicated in HCV antiviral resistance in many studies. NS5A antagonizes the IFN antiviral response in vitro, and one mechanism is via inhibition of a key IFN-induced enzyme, the double-stranded-RNA-activated protein kinase (PKR). In the present study we determined if NS5A uses other strategies to subvert the IFN system. Expression of full-length NS5A proteins from patients who exhibited a complete response (FL-NS5A-CR) or were nonresponsive (FL-NS5A-NR) to IFN therapy in HeLa cells had no effect on IFN induction of IFN-stimulated gene factor 3 (ISGF-3). Expression of mutant NS5A proteins lacking 110 (NS5A-DeltaN110), 222 (NS5A-DeltaN222), and 334 amino-terminal amino acids and mutants lacking 117 and 230 carboxy-terminal amino acids also had no effect on ISGF-3 induction by IFN. Expression of FL-NS5A-CR and FL-NS5A-NR did not affect IFN-induced STAT-1 tyrosine phosphorylation or upregulation of PKR and major histocompatibility complex class I antigens. However, NS5A expression in human cells induced interleukin 8 (IL-8) mRNA and protein, and this effect correlated with inhibition of the antiviral effects of IFN in an in vitro bioassay. NS5A induced transcription of a reporter gene driven by the IL-8 promoter, and the first 133 bp of the IL-8 promoter made up the minimal domain required for NS5A transactivation. NS5A-DeltaN110 and NS5A-DeltaN222 stimulated the IL-8 promoter to higher levels than did the full-length NS5A protein, and this correlated with increased nuclear localization of the proteins. Additional mutagenesis of the IL-8 promoter suggested that NF-kappaB and AP-1 were important in NS5A-DeltaN222 transactivation in the presence of tumor necrosis factor alpha and that NF-IL-6 was inhibitory to this process. This study suggests that NS5A inhibits the antiviral actions of IFN by at least two mechanisms and provides the first evidence for a biological effect of the transcriptional activity of the NS5A protein. During HCV infection, viral proteins may induce chemokines that contribute to HCV antiviral resistance and pathogenesis.
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PMID:Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. 1139 Jun 11

Hyperhomocysteinemia is an independent risk factor for atherosclerosis and atherothrombosis. While in vitro studies have revealed a number of homocysteine-mediated alterations in the thromboregulatory properties of endothelial cells, comparatively little is known about homocysteine-modulated smooth muscle cell function. We observed that exposure of human aortic smooth muscle cells to pathophysiologically relevant concentrations of homocysteine results in concentration-dependent increases in cytokine-induced MCP-1 and IL-8 secretion. RNase protection assays revealed that both MCP-1 and IL-8 mRNA concentrations are increased in homocysteine-treated smooth muscle cells when compared to cells activated with cytokines alone. Homocysteine treatment also increased cytosolic-to-nuclear translocation of the p65 and p50 subunits of the Rel/NF-kappaB family of transcription factors but had no effect on AP-1 activation. Cumulatively, these data suggest that homocysteine may increase monocyte recruitment into developing atherosclerotic lesions by upregulating MCP-1 and IL-8 expression in vascular smooth muscle cells.
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PMID:Homocysteine augments cytokine-induced chemokine expression in human vascular smooth muscle cells: implications for atherogenesis. 1140 9

Interleukin 1alpha (IL-1alpha) is an important regulatory cytokine, the release of which after an injury can induce activation of transcription factors nuclear factor (NF)kappaB and activator protein (AP-1), which promote expression of genes involved in cell survival, proliferation, and angiogenesis. IL-1alpha is expressed autonomously by head and neck squamous cell carcinomas (HNSCCs) and a variety of other cancers, raising the possibility that IL-1alpha may serve as an autocrine factor that stimulates the activation of prosurvival transcription factors and target genes in cancer. In this study, we examined the role of IL-1alpha in the activation of NFkappaB and AP-1, the expression of proangiogenic cytokine IL-8, and in the survival and proliferation of HNSCC cell lines. HNSCCs were found to secrete and respond to functional IL-1alpha, in that culture supernatant from a high IL-1alpha-secreting line, UM-SCC-11B, could induce secretion of cytokine IL-8 by a low IL-1alpha-secreting line, UM-SCC-9; and the induction of IL-8 secretion could be blocked by the anti-IL-1alpha-neutralizing antibody or the IL-1 receptor antagonist (IL-1RA). Furthermore, IL-1alpha could induce the expression of IL-8 through an autocrine mechanism, in that transfection of UM-SCC-9 cells with a plasmid encoding IL-1alpha resulted in the increased coexpression of IL-1alpha and IL-8; whereas transfection with a plasmid encoding IL-1RA lacking the secretory leader sequence led to the decreased coexpression of IL-1alpha and IL-8. IL-1alpha was found to induce coexpression of IL-8 through the activation of NFkappaB and AP-1, in that mutation of the NFkappaB site within the IL-8 promoter abolished autocrine- and recombinant IL-1alpha-induced IL-8 reporter gene activity, whereas mutation in AP-1 partially decreased IL-8 reporter gene activity in UM-SCC-9 cells. Intracellular expression of IL-1RA decreased NFkappaB reporter gene activity, indicating that endogenously expressed IL-1alpha contributes to constitutive NFkappaB activation in this HNSCC line. Expression of IL-1alpha affected survival of UM-SCC-9, inasmuch as transfection of cells with plasmid encoding IL-1alpha or IL-1RA led to the increased or decreased survival of cells cotransfected with a beta-galactosidase reporter gene, respectively. IL-1alpha was also found to promote the increased growth of UM-SCC-9 cells in vitro. We demonstrate that exogenous and endogenous IL-1alpha contributes to the transcriptional activation of NFkappaB and AP-1, to the expression of IL-8, and to cell survival and the growth of HNSCC in vitro.
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PMID:IL (interleukin)-1alpha promotes nuclear factor-kappaB and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas. 1141 May 24

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