Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transactivator protein, Tax, from the human T-cell leukemia virus type I (HTLV-I) transactivates both viral and cellular genes. Previously, we had shown that interleukin 8 (IL-8) is constitutively expressed in HTLV-I-infected cells and in cells transiently expressing Tax. We show here that the IL-8 promoter is Tax responsive in Jurkat T cells. Furthermore, using several deletion and mutated plasmids of the 5'-flanking regulatory region of the IL-8 gene linked to the luciferase gene as a reporter and mutant tax gene expression vectors, we have established that both AP-1 at -126 to -120 and nuclear factor (NF)-kappaB-like cis-element at -80 to -71 are essential and sufficient for the induction of the IL-8 gene by HTLV-I Tax. In addition, overexpression of the dominant-negative mutants of NF-kappaB inhibitor molecules, IkappaBalpha and IkappaBbeta, abolished the Tax-induced activation of IL-8 gene. Gel mobility shift assays detected proteins specifically binding to the AP-1 and NF-kappaB-like sites in Tax-expressing T-cell lines infected with HTLV-I. Similarly, the nuclear translocation of proteins specifically bound to these two motifs was shown in JPX-9 cells, a subclone of Jurkat cells, carrying the Tax sequences under the control of an inducible promoter. Taken together, these results suggest that the cooperation of transcription factors NF-kappaB and AP-1 is essential for transactivation of IL-8 gene by HTLV-I Tax.
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PMID:Human T-cell leukemia virus type I Tax transactivates human interleukin 8 gene through acting concurrently on AP-1 and nuclear factor-kappaB-like sites. 973 13

Interleukin-8 (IL-8) may play an important role in Helicobacter pylori infection-associated chronic active gastritis and peptic ulcer disease in human. We have recently reported that a gastric cancer cell line, MKN45, produced a massive amount of IL-8 upon coculture with live H. pylori. Moreover, H. pylori induced the activation of NF-kappaB as well as AP-1, leading to IL-8 gene transcription. In this study, we evaluated the effect of rebamipide, an antigastritis and antiulcer agent, on H. pylori-induced IL-8 production. Rebamipide inhibited the production of IL-8 in several gastric cancer cell lines infected with H. pylori. In addition, rebamipide suppressed H. pylori-induced IL-8 gene expression at the transcriptional level as revealed by northern blotting analysis and luciferase activity in cells that were transfected with a luciferase expression vector linked with a 5'-flanking region of the IL-8 gene (bp -133 to +44). Furthermore, rebamipide significantly suppressed the NF-kappaB activation by H. pylori infection. These results suggest that rebamipide may protect against the mucosal inflammation associated with H. pylori infection through inhibition of a proinflammatory cytokine, IL-8.
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PMID:Molecular analysis of suppression of interleukin-8 production by rebamipide in Helicobacter pylori-stimulated gastric cancer cell lines. 975 46

I-kappaBalpha is an intracellular protein that functions as a primary inhibitor of the proinflammatory transcription factor NF-kappaB. Induction of the stress response with heat shock was previously demonstrated to induce I-kappaBalpha gene expression. Because the stress response can also be induced by nonthermal stimuli, we determined whether induction of the stress response with prostaglandin A1 (PGA1) would induce I-kappaBalpha gene expression. Treatment of human bronchial epithelium (BEAS-2B cells) with PGA1 induced nuclear translocation of heat shock factor 1, thus confirming that PGA1 induces the stress response in BEAS-2B cells. Induction of the stress response with PGA1 increased I-kappaBalpha mRNA expression in a time-dependent manner and increased I-kappaBalpha peptide expression. Transient transfection assays involving a human I-kappaBalpha promoter-luciferase reporter construct demonstrated that induction of the stress response with PGA1 activated the I-kappaBalpha promoter. Induction of the stress response with PGA1 and concomitant induction of I-kappaBalpha were associated with inhibition of TNF-alpha-mediated secretion of interleukin 8 and with inhibition of TNF-alpha-mediated nuclear translocation and activation of NF-kappaB. These data demonstrate that induction of the stress response, by a nonthermal stimulus, increases I-kappaBalpha gene expression by a mechanism involving activation of the I-kappaBalpha promoter. Coupled with previous data demonstrating heat shock-mediated induction of I-kappaBalpha gene expression, these data suggest that I-kappaBalpha may be considered to be one of the stress proteins. The functional consequences of stress response-mediated I-kappaBalpha gene expression may involve attenuation of cellular proinflammatory responses.
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PMID:Induction of the stress response with prostaglandin A1 increases I-kappaBalpha gene expression. 976 80

Fine particles derived from diesel engines (diesel exhaust particles, DEP) have attracted attention, since their density in industrial countries seems related to the increased prevalence of pulmonary diseases. Previous studies have suggested that DEP have a potential to directly activate airway epithelial cells to produce and release inflammatory cytokines and mediators, and thus facilitate inflammatory responses in the lung. To elucidate the molecular mechanisms of their action, we studied here IL-8 gene expression, one of the important cytokines in inflammatory responses, by Northern blot analysis and run-on transcription assay. Suspended DEP (1-50 microgram/ml) increased the steady state levels of IL-8 mRNA, which was suggested to be largely due to increased transcriptional rates. Electrophoretic mobility shift assay demonstrated that DEP induced increased binding to the specific motif of NF-kappa B, but not of transcription factor AP-1. The luciferase reporter gene assay using wild-type and mutated NF-kappa B-binding sequences showed that DEP-induced NF-kappa B activation was involved in IL-8 transcription. Finally, both N-acetylcysteine and pyrrolidine dithiocarbamate attenuated the action of DEP on IL-8 mRNA expression, suggesting that oxidant-mediated pathway might be involved in its processes. These results suggested that DEP activate NF-kappa B, which might be an important mechanism of its potential to increase the expression of inflammatory cytokines in vitro.
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PMID:Diesel exhaust particles induce NF-kappa B activation in human bronchial epithelial cells in vitro: importance in cytokine transcription. 1020 11

The large T antigen of SV40 (LT) has been widely used to immortalize primary cells for various studies. In this study, synovial fibroblasts of a patient from rheumatoid arthritis (RA) were transformed with LT gene to analyze the effect of SV40-mediated transformation on the production of cytokines, such as IL-6, IL-8, and GM-CSF, that are under the control of interleukin-1 beta (IL-1 beta), a physiological inducer of nuclear factor kappa B (NF-kappa B). It was noted that the basal levels of GM-CSF and IL-8 were upregulated, whereas that of IL-6 was downregulated. Moreover, the extents of induction of these cytokines in response to IL-1 beta were markedly downregulated in synovial fibroblasts transformed by LT as compared from parental cells. Although IL-1 beta could translocate NF-kappa B to the nucleus in all cells, some of the transformed cells exhibited nuclear translocation of NF-kappa B even before the stimulation with IL-1 beta, suggesting that transformation of LT resulted in the constitutive activation of NF-kappa B, either directly or indirectly. In order to examine whether LT downregulate the kappa B-dependent gene expression, we performed the transient luciferase gene expression assay. We found that cotransfection of LT did not downregulate the kappa B-dependent gene expression that was stimulated with L-1 beta. These observations suggest that the apparent inhibitory effect of LT on the IL-1-induced expression of cytokines may not be through its direct action on the NF-kappa B transactivation.
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PMID:Alteration of the cellular response to interleukin-1 beta by SV40 large T antigen in rheumatoid synovial fibroblasts. 1047 Feb 56

NF-kappa B plays a critical role in the transcriptional regulation of proinflammatory gene expression in various cells. Cytokine-mediated activation of NF-kappa B requires activation of various kinases, which ultimately leads to the phosphorylation and degradation of I kappa B, the NF-kappa B cytoplasmic inhibitor. The food derivative curcumin has been shown to inhibit NF-kappa B activity in some cell types. In this report we investigate the mechanism of action of curcumin on cytokine-induced proinflammatory gene expression using intestinal epithelial cells (IEC). Curcumin inhibited IL-1 beta-mediated ICAM-1 and IL-8 gene expression in IEC-6, HT-29, and Caco-2 cells. Cytokine-induced NF-kappa B DNA binding activity, RelA nuclear translocation, I kappa B alpha degradation, I kappa B serine 32 phosphorylation, and I kappa B kinase (IKK) activity were blocked by curcumin treatment. Wound-induced p38 phosphorylation was not inhibited by curcumin treatment. In addition, mitogen-activated protein kinase/ERK kinase kinase-1-induced IL-8 gene expression and 12-O-tetraphorbol 12-myristate 13-acetate-responsive element-driven luciferase expression were inhibited by curcumin. However, I kappa B alpha degradation induced by ectopically expressed NF-kappa B-inducing kinase or IKK was not inhibited by curcumin treatment. Therefore, curcumin blocks a signal upstream of NF-kappa B-inducing kinase and IKK. We conclude that curcumin potently inhibits cytokine-mediated NF-kappa B activation by blocking a signal leading to IKK activity.
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PMID:Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. 1047 20

Topical vitamin D3 has relatively recently been introduced for the treatment of psoriasis. Synthetic vitamin D3 analogues with a high potential for inducing differentiation of cells, but with a low hypercalcemic effect have recently been developed. One such synthetic analogue of 1,25-dihydroxyvitamin D3 (calcitriol), 22-oxacalcitriol (OCT), is a novel agent for the topical treatment of psoriasis. The activity of OCT in vitro was investigated and compared with that of a series of vitamin D3 analogues as to their ability to inhibit murine T lymphocyte proliferation stimulated by con-A, to suppress IL-6 and IL-8 production by keratinocytes stimulated with IL-1alpha and TNFalpha, and to inhibit AP-1- and NFkappaB-dependent reporter gene expression. OCT inhibited the proliferation of lymphocytes and suppressed IL-8 and IL-6 production by keratinocytes to the same extent as the other vitamin D3 analogues. It also inhibited AP-1- and NFkappaB-controlled luciferase activity to the same extent as the other vitamin D3 analogues, which demonstrates its mechanism of action in the suppression of inflammatory processes.
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PMID:The action of a novel vitamin D3 analogue, OCT, on immunomodulatory function of keratinocytes and lymphocytes. 1054 80

Macrolide antibiotics are known to be effective for the treatment of chronic inflammatory airway diseases including diffuse panbronchiolitis, chronic bronchitis, and bronchial asthma. Other than having antimicrobial activities, macrolides have antiinflammatory effects, such as the inhibition of cytokine production. In the present study we investigated the effects of clarithromycin (CAM) on interleukin (IL)-8 gene expression and protein levels, using the human bronchial epithelial cell line BET-1A. Northern blot analyses showed that CAM inhibited tumor necrosis factor (TNF)-alpha-induced IL-8 gene expression in a dose- and incubation time-dependent manner. The half-life of IL-8 messenger RNA transcripts in TNF-alpha-treated BET-1A cells did not change with CAM. Transfection studies with BET-1A cells, using fusion genes composed of the 5'-flanking sequences of the IL-8 gene and a luciferase reporter gene, demonstrated potent promoter activity in a 174-bp segment (-130 to +44 bp relative to the transcription start site). This segment includes activator protein (AP)-1 and nuclear factor (NF)-kappaB-like sites, and exhibited its strongest response to TNF-alpha. TNF-alpha-induced promoter activity in this segment showed a significant repression by CAM. However, a 156-bp segment (-112 to +44 bp) that does not include an AP-1 site but includes an NF-kappaB-like site did not show a significant repression of TNF-alpha-induced promoter activity by CAM. Mutation of the AP-1 binding site abrogated the suppression by CAM of TNF-alpha-induced enhancement of luciferase activity. In accord with promoter analyses, an electrophoretic mobility shift assay showed that CAM repressed AP-1 binding in TNF-alpha-treated BET-1A cells; however, TNF-alpha induced both AP-1 and NF-kappaB binding activities in BET-1A cells. These data suggest that macrolides such as CAM repress IL-8 gene transcription mainly via the AP-1 binding site in human bronchial epithelial cells. Our findings provide a novel mechanism for the antiinflammatory function of macrolides, implicating a target for the development of new drugs for treating chronic airway inflammation.
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PMID:Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells. 1061 65

Interleukin (IL)-1beta signals through various adapter proteins and kinases that lead to activation of numerous downstream targets, including the transcription factors including NF-kappaB. In this study, we analyzed and characterized the effect of the differentiation of intestinal epithelial cells on IL-1beta-mediated NF-kappaB activation and IL-8 gene expression. We report that IL-8 mRNA accumulation and protein secretion were down-regulated in IL-1beta- and lipopolysaccharide-stimulated differentiated HT-29 cells (HT-29/MTX, where MTX is methotrexate) compared with undifferentiated cells (HT-29/p), whereas no differential effects were found following tumor necrosis factor (TNF)-alpha or phorbol myristate acetate stimulation. Cross-linking and affinity binding studies reveal that IL-1beta exclusively binds the type I receptor (IL-1RI) and not IL-1RII in both HT-29/p and HT-29/MTX cells. IL-1beta-mediated IkappaB kinase and c-Jun N-terminal kinase (JNK) activity were both diminished in differentiated HT-29 cells. DNA binding activity in differentiated HT-29 cells relative to HT-29/p cells was strongly reduced following IL-1beta exposure but not after TNF-alpha stimulation. The proximal IL-1 signaling molecule IL-1 receptor-associated kinase was not degraded in IL-1beta-stimulated HT-29 cells, in contrast to Caco-2 cells. kappaB-luciferase reporter gene activity was 16-fold higher following TNF receptor-associated factor-6 transfection after IL-1beta stimulation in HT-29/MTX cells. We conclude that cellular differentiation of HT-29 cells selectively impairs the IL-1beta signaling pathway inhibiting both NF-kappaB and JNK activity in response to IL-1beta. This relative unresponsiveness to IL-1beta may represent an important regulatory mechanism of differentiated intestinal epithelial cells.
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PMID:Cellular differentiation causes a selective down-regulation of interleukin (IL)-1beta-mediated NF-kappaB activation and IL-8 gene expression in intestinal epithelial cells. 1076 57

NF-kappa B plays a key role in the production of cytokines in inflammatory diseases. The effects of a novel T cell-specific NF-kappa B inhibitor, SP100030, were evaluated in cultured Jurkat cells and in murine collagen-induced arthritis (CIA). Chemical libraries were screened for NF-kappa B-inhibitory activity. SP100030, a compound identified in this process, inhibited NF-kappa B activation in PMA/PHA-activated Jurkat cells by EMSA at a concentration of 1 microM. Jurkat cells and the monocytic cell line THP-1 were transfected with an NF-kappa B promotor/luciferase construct and activated. SP100030 inhibited luciferase production in the Jurkat cells (IC50 = 30 nM). ELISA and RT-PCR confirmed that IL-2, IL-8, and TNF-alpha production by activated Jurkat and other T cell lines were inhibited by SP100030. However, cytokine expression was not blocked by the compound in THP-1 cells, fibroblasts, endothelial cells, or epithelial cells. Subsequently, DBA/1J mice were immunized with type II collagen. Treatment with SP100030 (10 mg/kg/day i.p. beginning on day 21) significantly decreased arthritis severity from onset of clinical signs to the end of the study on day 34 (arthritis score, 5.6 +/- 1.7 for SP100030 and 9.8 +/- 1.5 for control; p < 0.001). Histologic evaluation demonstrated a trend toward improvement in SP100030-treated animals. EMSA of arthritic mouse ankles in CIA showed that synovial NF-kappa B binding was suppressed in the SP100030-treated mice. SP100030 inhibits NF-kappa B activation in T cells, resulting in reduced NF-kappa B-regulated gene expression and decreased CIA. Its selectivity for T cells could provide potent immunosuppression with less toxicity than other NF-kappa B inhibitors.
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PMID:The effect of a T cell-specific NF-kappa B inhibitor on in vitro cytokine production and collagen-induced arthritis. 1090 76


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