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)

The present study aims at investigating the effects of mannitol and dimethylthiourea, known hydroxyl radical scavengers, on lipid peroxidation as an indicative of oxidative damage, NF-kappa B activation and IL-8 production by Helicobacter pylori in gastric epithelial cells. A human gastric epithelial cell line, AGS, treated with or without mannitol and dimethylthiourea, was incubated in the absence or the presence of H. pylori. As a result, H. pylori significantly stimulated the productions of lipid peroxide and IL-8. Treatment with H. pylori resulted in the activation of two species of NF-kappa B dimers (a p50/p65 heterodimer and a p50 homodimer). Mannitol and dimethylthiourea significantly inhibited lipid peroxide production, NF-kappa B complex formation and IL-8 production by H. pylori. In conclusion, mannitol and dimethylthiourea may attenuate H. pylori-induced gastric inflammation by inhibiting lipid peroxidation and NF-kappa B activation and thereby decreasing IL-8 production.
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PMID:Effects of mannitol and dimethylthiourea on helicobacter pylori-induced IL-8 production in gastric epithelial cells. 1047 80

Pulmonary epithelial cells, covering a 70-m2 surface area, have not previously been considered an important source of chemokines in pulmonary tuberculosis. We analyzed IL-8 secretion from A549 cells and primary normal human bronchial epithelial cells (NHBE) infected by Mycobacterium tuberculosis. Direct infection of A549 cells by M. tuberculosis caused IL-8 secretion of 7720 +/- 1610 pg/106 cells, but no IL-8 secretion from NHBE after 24 h. In contrast, conditioned media from M. tuberculosis-infected human monocytes (CoMTB) induced a much greater IL-8 secretion of 92,635 +/- 13,180 pg/106 A549 cells and 13,416 +/- 3,529 pg/106 NHBE after 24 h. CoMTB induced rapid IL-8 mRNA accumulation, which was stable over 24 h, compared with TNF-alpha-induced transcripts. CoMTB stimulated nuclear binding of p65, p50, and c-Rel subunits of NF-kappa B to IL-8 promoter sequences. Transient transfections with IL-8 promoter reporter constructs showed NF-kappa B binding-site mutations abolished IL-8 promoter activity while NF-IL-6 binding-site mutations decreased promoter activity to 50.2 +/- 6.3% of wild-type activity. IL-1R antagonist but not neutralizing anti-TNF-alpha inhibited epithelial cell IL-8 secretion, mRNA accumulation, and NF-kappa B binding. Recombinant IL-1 beta (2 ng/ml) induced similar levels of IL-8 secretion to CoMTB in both A549 cells and NHBE. Pulmonary epithelial cells are a major source of IL-8 in the initial host response to pulmonary tuberculosis. Such IL-8 secretion is NF-kappa B dependent, NF-IL-6 requiring, and activated by an IL-1-mediated pathway as a consequence of phagocytosis of M. tuberculosis by monocytes.
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PMID:Pulmonary epithelial cells are a source of IL-8 in the response to Mycobacterium tuberculosis: essential role of IL-1 from infected monocytes in a NF-kappa B-dependent network. 1049 Sep 95

We previously reported that human head and neck squamous cell carcinomas (HNSCCs) express the pro-inflammatory and pro-angiogenic cytokines interleukin (IL)-1alpha, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor in vitro and in vivo. The promoter region of the genes encoding these cytokines include binding sites for the transcription factors nuclear factor (NF) kappaB/Rel A, activator protein-1 (AP-1), and CCAAT enhancer-binding protein beta (C/EBPbeta, or NF-IL6), which have been reported to contribute to activation of these cytokine genes. In the study presented here, we examined the activation, composition, and function of these transcription factors in HNSCC cell lines that express pro-inflammatory cytokines, by using electrophoretic mobility shift and reporter-gene assays. Constitutive activation of NF-kappaB, AP-1, and NF-IL6 DNA-binding proteins was detected. Supershift analysis with antibodies specific for NF-kappaB, AP-1, and NF-IL6 binding proteins showed that the NF-kappaB-binding protein included p65/Rel A and p50; AP-1 activity included c-jun, junB, junD, and Fra-1; and NF-IL6 included C/EBPbeta. Mutational analysis of the NF-kappaB, AP-1, and NF-IL6 sites in the IL-8 promoter region showed that NF-kappaB and AP-1 sites contributed to constitutive IL-8 reporter activity in HNSCC. HNSCC lines that exhibited increased IL-8 secretion relative to simian virus 40-immortalized and primary keratinocyte cell lines also demonstrated a concordant increase in NF-kappaB reporter activity relative to nonmalignant keratinocytes. We concluded that the early transcription factors NF-kappaB, AP-1, and NF-IL6 are constitutively activated in human HNSCC cell lines and that NF-kappaB and AP-1 promote expression of the pro-inflammatory and pro-angiogenic cytokine IL-8 in HNSCC. The demonstration of the activation of these transcription factors will be helpful in defining the identity and role of these and other early gene products that contribute to pathogenesis of the malignant phenotype in HNSCC and in defining potential targets for pharmacologic and molecular therapy of HNSCC. Mol. Carcinog. 26:119-129, 1999. Published 1999 Wiley-Liss, Inc.
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PMID:Constitutive activation of transcription factors NF-(kappa)B, AP-1, and NF-IL6 in human head and neck squamous cell carcinoma cell lines that express pro-inflammatory and pro-angiogenic cytokines. 1050 55

Clostridium difficile causes an intense inflammatory colitis through the actions of two large exotoxins, toxin A and toxin B. IL-8 is believed to play an important role in the pathophysiology of C. difficile-mediated colitis, although the mechanism whereby the toxins up-regulate the release of IL-8 from target cells is not well understood. In this study, we investigated the mechanisms through which toxin A induces IL-8 secretion in human monocytes. We found that cellular uptake of toxin A is required for the up-regulation of IL-8, an effect that is not duplicated by a recombinant toxin fragment comprising the cell-binding domain alone. Toxin A induced IL-8 expression at the level of gene transcription and this effect occurred through a mechanism requiring intracellular calcium and calmodulin activation. Additionally, the effects of toxin A were inhibited by the protein tyrosine kinase inhibitor genistein, but were unaffected by inhibitors of protein kinase C and phosphatidylinositol-3 kinase. We determined that toxin A activates nuclear translocation of the transcription factors NF-kappa B and AP-1, but not NF-IL-6. NF-kappa B inhibitors blocked the ability of toxin A to induce IL-8 secretion, and supershift analysis indicated that the major isoform of NF-kappa B activated by the toxin is a p50-p65 heterodimer. This study is the first to identify intracellular signaling pathways and transcription factors involved in the C. difficile toxin-mediated up-regulation of IL-8 synthesis and release by target cells. This information should increase our understanding of the pathogenesis of C. difficile colitis and the nature of IL-8 gene regulation as well.
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PMID:Roles of intracellular calcium and NF-kappa B in the Clostridium difficile toxin A-induced up-regulation and secretion of IL-8 from human monocytes. 1055 38

A 3- to 8-fold stimulation of interleukin (IL)-8 gene expression by all-trans-retinoic acid (ATRA) was demonstrated in primary cultures of human and monkey tracheobronchial epithelial cells and BEAS-2B serum-sensitive cell line. The effect of ATRA on IL-8 gene expression is dose- and time-dependent. Using cycloheximide, it was observed that new protein synthesis was required for the stimulation. ATRA had no effect on IL-8 messenger RNA stability. A difference in nuclear run-on activity suggests that a transcriptional mechanism is involved in ATRA-enhanced IL-8 gene expression. Promoter-reporter gene transfection studies demonstrated ATRA enhanced IL-8 promoter activity, especially when cells were cotransfected with retinoic acid nuclear receptor-alpha expression vector. Deletion and site-directed mutagenesis analysis revealed the involvement of nuclear factor (NF)-kappaB binding site of the IL-8 gene in ATRA-enhanced promoter activity. Electrophoretic mobility shift assay (EMSA) demonstrated that ATRA enhanced DNA-NF-kappaB complex formation, especially with the p65 subunit. Western blot analysis demonstrated that ATRA did not enhance the protein amount of both the p50 and the p65 subunits in the nuclei. Because ATRA also enhances thioredoxin (TRX) gene expression, the effect of TRX on IL-8 gene expression was examined. IL-8 promoter activity was enhanced in transfected cells by the addition of TRX protein. Treatment of nuclear extracts with TRX also enhanced DNA- NF-kappaB complex formation as observed by EMSA, particularly the p65 subunit. Taking these data together, a novel mechanism is proposed in which ATRA activates promoter activity of IL-8 gene through TRX-dependent NF-kappaB activation.
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PMID:A novel mechanism of retinoic acid-enhanced interleukin-8 gene expression in airway epithelium. 1074 31

The present study aimed to investigate whether rebamipide, a novel antiulcer agent that has an oxygen radical scavenging activity, would inhibit lipid peroxidation, NF-kappaB activation, and IL-8 production by H. pylori. Human gastric epithelial cells (AGS and KATO III), treated with rebamipide or not were incubated in the absence or the presence of H. pylori. As a result, H. pylori significantly stimulated IL-8 production, which was similar to time course stimulation of lipid peroxidation. Other cytokines (IL-1alpha, IL-1beta, IL-6, TNF-alpha) were not stimulated by H. pylori. Treatment with H. pylori resulted in the activation of two species of NF-kappaB dimers (a p50/p65 heterodimer and a p50 homodimer). Rebamipide significantly inhibited lipid peroxidation as an indicative of oxidative damage, NF-kappaB complex formation, and IL-8 production by H. pylori. In conclusion, rebamipide may attenuate H. pylori-induced gastric inflammation by inhibiting lipid peroxidation and oxidant-mediated activation of NF-kappaB and thereby decreasing IL-8 production.
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PMID:Inhibition of lipid peroxidation, NF-kappaB activation and IL-8 production by rebamipide in Helicobacter pylori-stimulated gastric epithelial cells. 1074 42

Enteropathogenic Yersinia bacteria trigger the production of the proinflammatory chemokine IL-8, an important chemokine for the recruitment of polymorphonuclear leukocytes (PMN). Yersinia is resistant to phagocytosis by PMN, and the recruitment of these cells is thought to be part of a pathogenic strategy of Yersinia to establish infection by allowing the pathogen to gain access to, and disseminate within, host tissue. We report here that Yersinia expressing the outer membrane protein invasin triggers IL-8 production in epithelial cells. The 195 carboxyl-terminal amino acids of invasin when linked to latex beads are sufficient to trigger IL-8 production. By means of IL-8 promoter reporter gene assays and electrophoretic mobility shift assay experiments, the minimal optimal region of the IL-8 promoter responsive to invasin was identified and invasin-responsive control elements were characterized. Invasin-induced activation of the IL-8 promoter was found to be mediated through a previously identified NF-kappaB element. This NF-kappaB binding site preferentially binds Rel p65-p65 homodimers as well as some p50-p65 heterodimers in response to stimulation by invasin. Invasin-induced NF-kappaB activation correlated with degradation of IkappaBalpha and the inhibition of NF-kappaB by specific inhibitors of IkappaB activation blocked invasin-induced IL-8 secretion. Invasin-triggered IL-8 production does not depend on invasin-triggered uptake of bacteria, and is independent of a functional PI3-kinase. This report is the first to demonstrate the molecular basis of IL-8 production triggered by enteropathogenic bacteria. Together, these data elucidate the possible early pathomechanisms operating in Yersinia infection and may have implications for the design of novel therapeutics directed against this enteropathogen.
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PMID:Yersinia enterocolitica invasin protein triggers IL-8 production in epithelial cells via activation of Rel p65-p65 homodimers. 1092 81

Infection of human epithelial cells with human rhinovirus (HRV)-16 induces rapid production of several proinflammatory cytokines, including IL-8, IL-6, and GM-CSF. We evaluated the role of NF-kappaB in HRV-16-induced IL-8 and IL-6 production by EMSA using oligonucleotides corresponding to the binding sites for NF-kappaB in the IL-6 and IL-8 gene promoters. Consistent with the rapid induction of mRNA for IL-8 and IL-6, maximal NF-kappaB binding to both oligonucleotides was detected at 30 min after infection. NF-kappaB complexes contained p65 and p50, but not c-Rel. The IL-8 oligonucleotide bound recombinant p50 with only about one-tenth the efficiency of the IL-6 oligonucleotide, even though epithelial cells produced more IL-8 protein than IL-6. Neither the potent glucocorticoid, budesonide (10-7 M), nor a NO donor inhibited NF-kappaB binding to either cytokine promoter or induction of mRNA for either IL-8 or IL-6. Sulfasalazine and calpain inhibitor I, inhibitors of NF-kappaB activation, blocked HRV-16-induced formation of NF-kappaB complexes with oligonucleotides from both cytokines, but did not inhibit mRNA induction for either cytokine. By contrast, sulfasalazine clearly inhibited HRV-16 induction of mRNA for GM-CSF in the same cells. Thus, HRV-16 induces epithelial expression of IL-8 and IL-6 by an NF-kappaB-independent pathway, whereas induction of GM-CSF is at least partially dependent upon NF-kappaB activation.
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PMID:Role of NF-kappa B in cytokine production induced from human airway epithelial cells by rhinovirus infection. 1097 57

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

Increased levels of inflammatory cytokines such as interleukin (IL)-1 and IL-8 occur in the bronchoalveolar lavage fluid in various lung diseases. Cytokine gene expression is controlled by transcription factors such as nuclear factor-kappaB (NF-kappaB) which can be activated by a number of stimuli including the oxidants prevent. It was hypothesized that lipopolysaccharide (LPS)-induced IL-1beta secretion may be modulated by the intracellular thiol redox status of the cells. The effect of the antioxidant compound, N-acetyl-L-cysteine (NAC), on IL-1beta release and regulation of NF-kappaB in a human myelo-monocytic cell line (THP-1) differentiated into macrophages was studied. LPS (10 microg x mL(-1)) increased IL-1beta release at 24 h compared to control levels (p<0.001). NAC (5 mM) also enhanced LPS-induced IL-1beta release from THP-1 cells (p<0.001). In addition, treatment of cells with cycloheximide, an inhibitor of protein synthesis, inhibited the NAC-mediated IL-1beta release. Under the same conditions, NF-kappaB binding was activated by LPS and NAC increased this LPS-mediated effect. Western blot analysis revealed that NAC treatment leads to an increase in p50 and p65 protein synthesis. These data indicate that N-acetyl-L-cysteine modulates interleukin-1kappa release by increasing levels of the homo- and heterodimeric forms of nuclear factor-kappaB.
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PMID:Regulation of lipopolysaccharide-mediated interleukin-1beta release by N-acetylcysteine in THP-1 cells. 1115 95

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