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)

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

Constitutive IKK activity associated with increased IkappaBalpha phosphorylation and degradation contribute to the high level of endogenous nuclear factor-kappaB (NF-kappaB) activation in Hs294T melanoma cells as compared with RPE cells (R. L. Shattuck-Brandt and A. Richmond, Cancer Res., 57: 3032-3039, 1997; M. N. Devalaraja et al., Cancer Res., 59: 1372-1377, 1999). To determine whether this endogenous NF-kappaB activation was characteristic of melanoma, we examined the level of constitutive activation of NF-kappaB in a number of melanoma cell lines. We demonstrate here that eight melanoma cell lines exhibit increased IkappaB kinase (IKK) activity, enhanced phosphorylation of IkappaBalpha and p65, and enhanced nuclear localization of p65/p50 in comparison to normal human epidermal melanocytes. The chemokines, CXC ligand 1 (CXCL1) and CXCL8, but not CXCL5, are highly expressed in most of the melanoma cell lines, suggesting that the constitutive production of chemokines is highly correlated to endogenous NF-kappaB activity. Our failure to observe a direct relationship between the fold activation of IKK, CXCL1, or CXCL8 mRNA levels and secretion of these chemokines into the culture medium suggest that regulation of chemokine expression also occurs at the posttranscription level of mRNA stability and/or translational control. Moreover, recombinant CXCL1 can directly induce IKK activity in normal human epidermal melanocytes in a concentration-dependent manner after up-modulation of CXCL1 protein expression, whereas inhibition of IKKbeta activity results in down-modulation of CXCL1 protein expression. Finally, CXCL1 antibody blocks IKK activity and inhibits the proliferation of melanoma cells to further support the concept that the constitutive activation of NF-kappaB and autocrine effects of CXCL1 play an important role in the pathogenesis of melanoma.
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PMID:Constitutive IkappaB kinase activity correlates with nuclear factor-kappaB activation in human melanoma cells. 1140 69

Since the NF-kappaB/relA transcription factor is constitutively activated in human prostate cancer cells, we determined whether blocking NF-kappaB/relA activity in human prostate cancer cells affected their angiogenesis, growth, and metastasis in an orthotopic nude mouse model. Highly metastatic PC-3M human prostate cancer cells were transfected with a mutated IkappaBalpha (IkappaBalphaM), which blocks NF-kappaB activity. Parental (PC-3M), control vector-transfected (PC-3M-Neo), and IkappaBalphaM-transfected (PC-3M-IkappaBalphaM) cells were injected into the prostate gland of nude mice. PC-3M and PC-3M-Neo cells produced rapidly growing tumors and regional lymph node metastasis, whereas PC-3M-IkappaBalphaM cells produced slow growing tumors with low metastatic potential. NF-kappaB signaling blockade significantly inhibited in vitro and in vivo expression of three major proangiogenic molecules, VEGF, IL-8, and MMP-9, and hence decreased neoplastic angiogenesis. Inhibition of NF-kappaB activity in PC-3M cells also resulted in the downregulation of MMP-9 mRNA and collagenase activity, resulting in decreased invasion through Matrigel. Collectively, these data suggest that blockade of NF-kappaB activity in PC-3M cells inhibits angiogenesis, invasion, and metastasis.
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PMID:Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. 1146 85

Geldanamycin is a benzoquinone ansamycin with multiple pharmacologic properties. Recent data demonstrated that geldanamycin conferred protection in an animal model of inflammation-associated acute lung injury. In the current study, we investigated the effects of geldanamycin on interleukin (IL)-8 gene expression and nuclear factor (NF)-kappaB activation. Geldanamycin inhibited tumor necrosis factor (TNF)-alpha-mediated IL-8 gene expression in A549 human respiratory epithelial cells as measured by enzyme-linked immunosorbent assay and Northern blot analyses. In cells transiently transfected with an IL-8 promoter-luciferase reporter plasmid, geldanamycin inhibited TNF-alpha-mediated luciferase activity. Geldanamycin inhibited TNF-alpha-mediated NF-kappaB activation as measured by electromobility shift assays and transient transfections with a NF-kappaB-dependent luciferase reporter plasmid. In contrast, geldanamycin did not affect TNF-alpha-mediated degradation of the NF-kappaB inhibitory protein IkappaBalpha and did not block nuclear translocation of the NF-kappaB p65 subunit as measured by Western blot analyses. Geldanamycin added directly to nuclear extracts of TNF-alpha-treated cells reduced the formation of the NF-kappaB/DNA complex. These results demonstrate that geldanamycin inhibits TNF-alpha-mediated IL-8 gene expression in A549 cells by inhibiting activation of the IL-8 promoter. The mechanism of inhibition involves inhibition of NF-kappaB activation, which is independent of IkappaBalpha degradation or p65 nuclear translocation. Geldanamycin appears to directly inhibit the ability of NF-kappaB to bind DNA. The observed in vitro effects could account, in part, for the anti-inflammatory properties of geldanamycin observed in vivo.
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PMID:Geldanamycin inhibits NF-kappaB activation and interleukin-8 gene expression in cultured human respiratory epithelium. 1147 80

Monocyte phagocytosis of pathogens or inflammatory debris leads to chemokine secretion and heralds the influx of leukocytes to the site of injury. Persistent chemokine secretion can lead to tissue damage. However, the mechanisms by which phagocytosis regulates chemokine synthesis remain poorly understood. As a first step, we have studied regulation of interleukin (IL) 8 gene expression after interaction with zymosan or latex. IL-8 secretion was consistently one- or twofold higher after incubation with zymosan than with latex. Nuclear factor (NF) kappaB translocation to the nucleus was induced by zymosan but not latex, indicating that its translocation is dependent on the nature of the phagocytic stimulus. NFkappaB activation coincided with IkappaBalpha degradation but had no effect on processing of NFkappaB1/p105, the precursor of the NFkappaB protein p50. The NFkappaB inhibitor gliotoxin abrogated zymosan-induced IL-8 synthesis in peripheral blood monocytes, further demonstrating that the induction of IL-8 mRNA by zymosan is NFkappaB dependent. SB203580 inhibition of the p38 mitogen-activated protein kinase (MAPK) pathway significantly decreased zymosan-induced IL-8 mRNA accumulation. Inhibitors of protein kinases A and C or tyrosine kinases had no significant effect on zymosan-induced IL-8 synthesis. These data indicate that p38 MAPK and NFkappaB are critical in controlling zymosan-induced IL-8 secretion.
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PMID:Regulation of interleukin-8 gene expression after phagocytosis of zymosan by human monocytic cells. 1152 95

Enteropathogenic Escherichia coli (EPEC) alters many functions of the host intestinal epithelia. Inflammation is initiated by activation of nuclear factor (NF)-kappaB, and paracellular permeability is enhanced via a Ca2+- and myosin light-chain kinase (MLCK)-dependent pathway. The aims of this study were to identify signaling pathways by which EPEC triggers inflammation and to determine whether these pathways parallel or diverge from those that alter permeability. EPEC-induced phosphorylation and degradation of the primary inhibitor of NF-kappaB (IkappaBalpha) were tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta independent. In contrast to Salmonella typhimurium, EPEC-stimulated IkappaBalpha degradation and IL-8 expression did not require Ca2+. Instead, extracellular signal-regulated kinase (ERK)-1/2 was significantly and rapidly activated. ERK1/2 inhibitors attenuated IkappaBalpha degradation and IL-8 expression. Although ERK1/2 can activate MLCK, its inhibition had no impact on EPEC disruption of the tight junction barrier. In conclusion, EPEC-induced inflammation 1) is TNF-alpha and IL-1beta receptor independent, 2) utilizes pathways differently from S. typhimurium, 3) requires ERK1/2, and 4) employs signals that are distinct from those that alter permeability. This is the first time that EPEC-activated signaling cascades have been linked to independent functional consequences.
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PMID:EPEC-activated ERK1/2 participate in inflammatory response but not tight junction barrier disruption. 1155 8

NF-kappaB/Rel transcription factors have been implicated in the differentiation of monocytes to either dendritic cells (DCs) or macrophages, as well as in the maturation of DCs from antigen-processing to antigen-presenting cells. Recent studies of the expression pattern of Rel proteins and their inhibitors (IkappaBs) suggest that their regulation during this differentiation process is transcriptional. To investigate differential gene expression between macrophages and DCs, we used commercially available gene microarrays (GEArray KIT), which included four of the NF-kappaB/Rel family genes (p50/p105, p52/p100, RelB, and c-rel) and 32 additional genes either in the NF-kappaB signal transduction pathway or under transcriptional control of NF-kappaB/Rel factors. To generate macrophages and DCs, human adherent peripheral blood monocytes were cultured with M-CSF or GM-CSF + IL-4 respectively for up to 8 days. DCs (and in some experiments, macrophages) were treated with lipopolysaccharide (LPS) for the last 48 h of culture to induce maturation. Cells were harvested after 7 days, cDNA was prepared and radiolabeled with alpha-(32)P-dCTP, then hybridized to gene arrays containing specific gene probes. beta-actin and GAPDH or PUC18 oligonucleotides served as positive or negative controls, respectively. The expression of all four NF-kappaB/Rel family genes examined was significantly upregulated in maturing DCs compared to macrophages. The strongest difference was observed for c-rel. RT-PCR determinations of c-rel, RelB, and p105 mRNAs confirmed these observations. Among the 32 NF-kappaB/Rel pathway genes, 14 were upregulated in mature DCs compared to macrophages. These genes were IkappaBalpha, IKK-beta, NIK, ICAM-1, P-selectin, E-selectin, TNF-alpha, TNFR2, TNFAIP3, IL-1alpha, IL-1R1, IL-1R2, IRAK, and TANK. By contrast, only mcp-1 (monocyte chemotactic protein 1) was upregulated in macrophages compared to DCs. NF-kappaB pathway genes upregulated in DCs compared to macrophages were constitutively expressed in monocytes then selectively downregulated during macrophage but not DC differentiation. LPS did not induce expression of most of these genes in macrophages but LPS did induce upregulation of IL-8 in mature macrophages. We conclude that NF-kappaB/Rel family genes, especially c-rel, are selectively expressed during differentiation of monocytes towards DCs. Moreover, this differential expression is associated both with activation of different NF-kappaB signal transduction pathways in DCs and macrophages and with expression of a unique subset of genes in DCs that are transcriptionally targeted by NF-kappaB/Rel factors. The results illustrate the ability of the NF-kappaB pathway to respond to differentiation stimuli by activating in a cell-specific manner unique signalling pathways and subsets of NF-kappaB target genes.
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PMID:Expression of different NF-kappaB pathway genes in dendritic cells (DCs) or macrophages assessed by gene expression profiling. 1157 45

The authors have recently shown that the transcription factor nuclear factor-kappaB (NF-kappaB) is a central mediator in the NaCl-mediated interleukin (IL)-8 production by human airway epithelial cells. In this study, it was investigated whether Physiomer, an isotonic sea water-derived solution commercialized for cleaning the nasal mucosa, impaired the chemokine IL-8 expression and secretion by human respiratory epithelial cells compared with that obtained with an isotonic 9% NaCl solution. Primary human bronchial gland (HBG) epithelial cells were incubated either in Physiomer or in a NaCl 9% solution and activated either with 20 ng x mL(-1) tumour necrosis factor-alpha, or IL-1beta, respectively. Physiomer significantly reduced the IL-8 protein release in basal and activated HBG cells in comparison with that obtained with the 9% NaCl solution. In contrast to the effects of Physiomer observed on resting HBG cells, Physiomer did not significantly reduce the level of phosphorylation of the NF-kappaB inhibitor protein IkappaBalpha or the steady-state IL-8 messenger ribonucleic acid levels in activated HBG cells, suggesting that Physiomer would have a post-transcriptional effect on IL-8 expression in activated HBG cells. The authors conclude that Physiomer is potentially useful in the reduction of airway mucosal inflammation.
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PMID:Physiomer reduces the chemokine interleukin-8 production by activated human respiratory epithelial cells. 1171 71

Flagellin, the monomeric subunit of flagella, is an inducer of proinflammatory mediators. Bacterial flagellin genes have conserved domains (D1 and D2) at the N terminus and C terminus and a middle hypervariable domain (D3). To identify which domains induced proinflammatory activity, r6-histidine (6HIS)-tagged fusion constructs were generated from the Salmonella dublin (SD) fliC flagellin gene. A full-length r6HIS SD flagellin (6HIS flag) induced IkappaBalpha loss poststimulation and NF-kappaB activation in Caco-2BBe cells and was as potent as native-purified SD flagellin. IFN-gamma-primed DLD-1 cells stimulated with 1 microg/ml of 6HIS flag induced high levels of NO (60 +/- 0.95 microM) comparable to the combination of IL-1beta and IFN-gamma (77 +/- 1.2) or purified native SD flag (66.3 +/- 0.98). Selected rSD flagellin proteins representing the D1, D2, or D3 domains alone or in combination were tested for proinflammatory properties. Fusion proteins representing the D3, amino, or carboxyl regions alone did not induce proinflammatory mediators. The results with a recombinant protein containing the amino D1 and D2 and carboxyl D1 and D2 separated by an Escherichia coli hinge (ND1-2/ECH/CD2) indicated that D1 and D2 were bioactive when coupled to an ECH element to allow protein folding. This chimera, but not the hinge alone, induced IkappaBalpha degradation, NF-kappaB activation, and NO and IL-8 production in two intestinal epithelial cell lines. ND1-2/ECH/CD2-1 also induced high levels of TNF-alpha (900 pg/ml) in human monocytes comparable to native SD flagellin (991.5 pg/ml) and 6HIS flag (987 pg/ml). The potent proinflammatory activity of flagellin, therefore, resides in the highly conserved N and C D1 and D2 regions.
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PMID:Salmonella flagellin-dependent proinflammatory responses are localized to the conserved amino and carboxyl regions of the protein. 1173 21

Neutrophil-dependent inflammation dependent on monosodium urate (MSU) crystal-induced IL-8 expression occurs in gout. MSU crystals activate phagocyte Src family tyrosine kinases and the serine/threonine kinase p70s6k. Thus, using monocytic THP-1 cells, we assessed the potential for Src family kinases and p70s6k to mediate MSU-induced IL-8 expression. MSU crystals induced phosphorylation of p70s6k and the Src kinases c-Src, Lyn, Hck, and Fyn. IL-8 expression was attenuated more by the Src kinase inhibitor PP1 than by the p70s6k inhibitor rapamycin. PP1 inhibited crystal-induced phosphorylation of ERK1/2 and IkappaBalpha and suppressed IkappaB kinase (IKK) activation and NF-kappaB binding to the IL-8 promoter, signals that mediate MSU-induced IL-8 expression. Transfection of the native Src inhibitor, C-terminal Src kinase (Csk), also suppressed crystal-induced c-Src, ERK1/2, and IkappaBalpha phosphorylation and IL-8 expression. We conclude that Src family tyrosine kinase signaling plays a significant role in MSU crystal-induced IL-8 expression via stimulation of ERK1/2 pathway and NF-kappaB activation.
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PMID:Src family protein tyrosine kinase signaling mediates monosodium urate crystal-induced IL-8 expression by monocytic THP-1 cells. 1173 59


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