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)

Human herpesvirus 8 (HHV-8) encodes a viral FLICE inhibitory protein (vFLIP), called K13, with homology to the prodomain of caspase 8. K13 has been postulated to protect virally infected cells against death receptor-induced apoptosis. We report that K13 leads to constitutive upregulation of IL-8 secretion by transcriptional upregulation of its promoter. K13-induced IL-8 promoter activation is dependent on an intact NF-kappaB-binding site and is associated with increased binding of classical NF-kappaB pathway subunits p65, c-Rel and p50, respectively. IL-8 production is defective in K13 mutants defective in classical NF-kappaB activation and is blocked by genetic and pharmacological inhibitors of this pathway. In contrast, K13 failed to activate the JNK/AP-1 pathway and deletion of AP-1-binding site in the IL-8 promoter or use of a specific JNK inhibitor had only a partial effect on K13-induced IL-8 promoter activation. Collectively, above results demonstrate that K13 is a major mediator of IL-8 production and therapeutic agents targeting K13-induced NF-kappaB pathway may have a role in the treatment of conditions in which HHV-8-induced IL-8 production plays a pathogenic role.
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PMID:Induction of IL-8 expression by human herpesvirus 8 encoded vFLIP K13 via NF-kappaB activation. 1641 26

Herpetic epithelial and stromal keratitis is a sight-threatening ocular infection. To study the role of the epithelium in the innate response to herpes simplex virus 1 (HSV-1) infection of the cornea, we used a telomerase-immortalized human corneal epithelial cell (HCEC) line, HUCL, and primary HCECs as a model and infected the cells with HSV-1 (KOS strain). HSV-1 infection of HCECs resulted in a two-phase activation of nuclear factor-kappaB (NF-kappaB), JNK and p38, with the first peak at 1-4 hr and a second peak at 8 hr. Concomitant with the first peak of activation, transcriptional expression of interleukin (IL)-6, IL-8, tumour necrosis factor (TNF)-alpha and interferon (IFN)-beta was rapidly induced in HSV-1-infected cells. HSV-1 infection also induced the production of IL-6, IL-8, and TNF-alpha in both HUCL cells and primary HCECs. Coincident with the second phase of NF-kappaB activation in HSV-1-infected HCECs, the expression of Toll-like receptor 7 (TLR7) was induced, whereas the level of TLR3 was greatly down-regulated. Thus, in response to HSV-1 infection, HCECs produce proinflammatory cytokines, leading to infiltration, and IFNs to enhance the antiviral activity in the cornea, probably through sequential activation of TLRs.
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PMID:Herpes simplex virus 1 infection induces the expression of proinflammatory cytokines, interferons and TLR7 in human corneal epithelial cells. 1642 52

IL-20 belongs to the IL-10 family and is involved in the pathogenesis of keratinocyte hyperproliferation in vivo. Endothelial cells express IL-20 receptors. To explore the function of IL-20 on endothelial cells, we treated human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells (HMECs) with human IL-20 and analyzed its effect on endothelial cells. IL-20 induced proliferation of endothelial cells and the activity was specifically blocked by anti-human-IL-20 monoclonal antibody and soluble (s)IL-20 receptor (R)1 and sIL-20R2. An alternatively spliced variant of IL-20 was isolated and also was shown to induce proliferation of HUVECs and HMECs. Treatment of HUVECs with both IL-10 and IL-20 demonstrated that IL-10 antagonized the activity of IL-20 because it diminished IL-20-induced proliferation of HUVECs. IL-20 significantly induced HUVECs migration and vascular tube formation on Matrigel in vitro. In vivo, IL-20 also enhanced tumor angiogenesis. Incubation of IL-20 with HUVECs induced transcripts of bFGF, VEGF, MMP-2, MMP-9, and IL-8. Furthermore, incubation of HUVECs with IL-20 induced phosphorylation of ERK1/2, p38, and JNK. Thus, IL-20 is a pleiotropic cytokine and promotes angiogenesis.
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PMID:Interleukin-20 promotes angiogenesis in a direct and indirect manner. 1651 54

IL-22 is produced by activated T cells and signals through a receptor complex consisting of IL-22R1 and IL-10R2. The aim of this study was to analyze IL-22 receptor expression, signal transduction, and specific biological functions of this cytokine system in intestinal epithelial cells (IEC). Expression studies were performed by RT-PCR. Signal transduction was analyzed by Western blot experiments, cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and Fas-induced apoptosis by flow cytometry. IEC migration was studied in wounding assays. The IEC lines Caco-2, DLD-1, SW480, HCT116, and HT-29 express both IL-22 receptor subunits IL-22R1 and IL-10R2. Stimulation with TNF-alpha, IL-1beta, and LPS significantly upregulated IL-22R1 without affecting IL-10R2 mRNA expression. IL-22 binding to its receptor complex activates STAT1/3, Akt, ERK1/2, and SAPK/JNK MAP kinases. IL-22 significantly increased cell proliferation (P = 0.002) and phosphatidylinsitol 3-kinase-dependent IEC cell migration (P < 0.00001) as well as mRNA expression of TNF-alpha, IL-8, and human beta-defensin-2. IL-22 had no effect on Fas-induced apoptosis. IL-22 mRNA expression was increased in inflamed colonic lesions of patients with Crohn's disease and correlated highly with the IL-8 expression in these lesions (r = 0.840). Moreover, IL-22 expression was increased in murine dextran sulfate sodium-induced colitis. IEC express functional receptors for IL-22, which increases the expression of proinflammatory cytokines and promotes the innate immune response by increased defensin expression. Moreover, our data indicate intestinal barrier functions for this cytokine-promoting IEC migration, which suggests an important function in intestinal inflammation and wound healing. IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and IEC migration.
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PMID:IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. 1653 74

Fludarabine is a nucleoside analogue that has been successfully employed for the treatment of low-grade lymphoid malignancies and, more recently, in nonmyeloablative preparative regimens for stem cell transplantation, due to its strong cytotoxic activity on lymphocytes. In this paper, we show that fludarabine can also induce pro-inflammatory stimulation of monocytic cells, as evaluated by increased expression of ICAM-1 and IL-8 release. To study the mechanisms involved, we employed selective inhibitors of MAPK and NF-kappaB pathways, both of which have been implicated in the modulation of ICAM-1 and IL-8. Our results showed that fludarabine effects were mediated through the activation of ERK and were independent on p38, JNK or NF-kappaB pathways. By Western blotting analysis we corroborated that fludarabine induced a rapid activation of ERK that was sustained for at least 30 min. Moreover, pro-inflammatory activation of monocytic cells by fludarabine was largely attenuated by coadministration of the free radical scavenger N-acetylcysteine suggesting the involvement of reactive oxygen species in fludarabine effects. Finally, we showed that fludarabine induced the activation of the transcription factor AP-1 not only in monocytic cells but also in non-proliferating lymphocytes from chronic lymphocytic leukemia. It is possible that some of fludarabine side effects in vivo may be attributed to cell activation/differentiation rather than induction of apoptosis.
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PMID:Fludarabine induces pro-inflammatory activation of human monocytic cells through a MAPK/ERK pathway. 1654 1

Tryptase is involved in proteinase-activated receptor-2 (PAR-2) mediated up-regulation of IL-8 expression. The present report showed the effects of tryptase on gene expression and activation, including up-regulation IL-8 expression. The expression of mRNA for NF-kappaB first increased at 1 h after tryptase-treatment (1 ng/ml) and reached the plateau after 4 h. The NF-kappaB mRNA increased by 3-fold (n = 3, P < 0.05), AP-1 by 2-fold (n = 3, P < 0.05), and PKB by 10-fold (n = 3, P < 0.05). However, tryptase-treatment did not affect the expression of JNK and p38 MAPK when compared with control cells at mRNA level. Furthermore, in addition to increasing phosphorylation of p38 MAPK, tryptase-treatment also increased phosphorylation of PKB by 2-fold at 15 min following the treatment. The up-regulation and phosphorylation of PKB by tryptase could be abolished by either phosphoinositol-3-kinase (PI3K) inhibitor (LY294002) at 10 microM or antisense PKB cDNA transfection. The up-regulation of NF-kappaB expression could be inhibited by LY294002 and antisense PKB cDNA. These results indicate that tryptase can activate PI3K-PKB pathway and enhance IL-8 expression.
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PMID:Tryptase activates PKB in inflammatory reaction in ECV304 cells. 1656

Nuclear factor-kappaB (NF-kappaB) and AP-1 nuclear transcriptional factors regulate expression of multiple genes involved in tumor growth, metastasis and angiogenesis; however, the relative contribution of each factor to cancer initiation and progression has not been established. Prostate carcinogenesis involves transformation of normal zinc-accumulating epithelial cells to malignant cells that do not accumulate zinc. Whereas activation of both NF-kappaB and AP-1 has been implicated in prostate cancer development and growth, we tested the relative effects of zinc supplementation on these important transcriptional factors. Herein, we demonstrate that physiological levels of zinc inhibit NF-kappaB but augment activities of AP-1 in DU-145 and PC-3 human prostate cancer cells. Additionally, we show that chelation of zinc with membrane-permeable zinc chelator, N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) abolishes this effect. We further propose a potential mechanism for this observation by demonstrating that zinc supplementation induces phosphorylation of the members of three major MAPK subfamilies regulating AP-1 and NF-kappaB activation (ERK 1/2, JNK and p38) while blocking TNF-alpha-mediated degradation of the inhibitory subunit I kappa B alpha and nuclear translocation of RelA in prostate cancer cells. VEGF, IL-6, IL-8 and MMP-9 are major pro-angiogenic and pro-metastatic molecules whose promoter regions contain binding sites for both NF-kappaB and AP-1. These cytokines have been associated with negative prognostic features in prostate cancer. We demonstrate that treatment of human prostate cancer cell lines with zinc reduces expression of VEGF, IL-6, IL-8 and MMP-9. We further show that zinc reduces expression of intercellular adhesion molecule-1 and functionally suppresses tumor cell invasiveness and adhesion. Therefore, the ability of zinc supplementation to inhibit NF-kappaB supercedes zinc-mediated activation of AP-1 family members. Upregulation of intracellular zinc levels may have important implications for inhibiting the angiogenic and metastatic potentials of malignant cells, predominantly through suppression of NF-kappaB signaling.
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PMID:Diverse effects of zinc on NF-kappaB and AP-1 transcription factors: implications for prostate cancer progression. 1660 32

Mycoplasma can establish latent infections and are associated with arthritis, leukemia, and chronic lung disease. We developed an experimental model in which lung cells are deliberately infected with Mycoplasma fermentans. Human lung fibroblasts (HLF) were exposed to live M. fermentans and immune-modulating cytokine release was assessed with and without known inducers of cytokine production. M. fermentans increased IL-6, IL-8/CXCL8, MCP-1/CCL2, and Gro-alpha/CXCL1 production. M. fermentans interacted with TNF-beta to release more IL-6, CXCL8, and CXCL1 than predicted by the responses to either stimulus alone. The effects of live infection were recapitulated by exposure to M. fermentans-derived macrophage-activating lipopeptide-2 (MALP-2), a Toll-like receptor-2- and receptor-6-specific ligand. The synergistic effect of combined stimuli was more pronounced with prolonged incubations. Preexposure to TNF-beta sensitized the cells to subsequent MALP-2 challenge, but preexposure to MALP-2 did not alter the IL-6 response to TNF-beta. Exposure to M. fermentans or MALP-2 did not enhance nuclear localization, DNA binding, or transcriptional activity of NF-kappaB and did not modulate early NF-kappaB activation in response to TNF-beta. Application of specific inhibitors of various MAPKs suggested that p38 and JNK/stress-activated protein kinase were involved in early IL-6 release after exposure to TNF-beta and M. fermentans, respectively. The combined response to M. fermentans and TNF-beta, however, was uniquely sensitive to delayed application of SP-600125, suggesting that JNK/stress-activated protein kinase contributes to the amplification of IL-6 release. Thus M. fermentans interacts with stimuli such as TNF-beta to amplify lung cell production of immune-modulating cytokines. The mechanisms accounting for this interaction can now be dissected with the use of this in vitro model.
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PMID:Mycoplasma fermentans and TNF-beta interact to amplify immune-modulating cytokines in human lung fibroblasts. 1675 Dec 26

We examined the effects of different bacterial doses of Neisseria gonorrhoeae on the cytokine response of primary human monocytes. The data indicate that a low multiplicity of infection (MOI) challenge (MOI = 0.1) results in substantial production of IL-8 and other chemokines/cytokines, in the absence of significant TNF-alpha production. Positive control challenges (MOI = 10) induced levels of IL-8 that were comparable to the low MOI challenges, but now induced significant levels of TNF-alpha. Induction of IL-8 expression in low MOI challenges was not mediated by an autocrine response as pretreatment of monocytes with neutralizing Abs against TNF-alpha or IL-1beta had no effect on IL-8 expression. IL-8 induction resulting from gonococcal challenge was shown to require NF-kappaB activation, though this activation was limited by the inoculating dose. These data indicate that IL-8 induction results from direct contact between bacteria and monocytes. Analysis of the overall cytokine profile revealed patterns of expression for growth-regulated oncogene, MCP-1, and IL-6 that were similar to IL-8. Analysis of various MAPKs indicated that low MOI challenges were able to efficiently activate both the ERK and p38 pathways, but in contrast to positive control samples, failed to activate the JNK pathway. A lack of phosphorylated JNK leads to decreased production of AP-1 dimers, transcription factors that are critical for efficient transcription of TNF-alpha. Therefore, we propose a mechanism where a low MOI gonococcal challenge results in diminished AP-1 activity and TNF-alpha production while IL-8 levels remain constant.
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PMID:TNF-alpha-independent IL-8 expression: alterations in bacterial challenge dose cause differential human monocytic cytokine response. 1681 92

Intestinal epithelial cells (IECs) have been known to produce galactose-alpha1,4-galactose-beta1,4-glucose ceramide (Gb3) which plays a pivotal role in the mucosal immune response. In particular, Shiga-like toxins (Stx) can induce apoptosis of IECs in the development of hemolytic uremic syndrome (HUS) through binding on Gb3. Therefore, it has been hypothesized that down-regulation of Gb3 (or binding of Stx) prevents Stx from damaging in IECs. This study investigated whether curcumin, having various biological properties such as being anti-bacterial, anti-viral and anti-cancer, could decrease binding of Stx and the related signal pathway. Curcumin significantly inhibited the binding of Stx and the production of Gb3 synthase (GalT6) mRNA in HT29 IECs stimulated with TNF-alpha and IL-1beta. Additionally, curcumin was able to inhibit mitogen-activated protein kinases (MAPKs), such as p38 and JNK, but not ERK1/2, degradation of IkappaB or translocation of NF-kappaB p65. Furthermore, curcumin significantly attenuated Stx-1 induced cell death and IL-8 expression. In summary, these data link Gb3 expression in HT29 cells stimulated with TNF-alpha and IL-1beta and suggest that blocking of Stx-binding by curcumin may prevent the Stx-associated HUS.
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PMID:Curcumin decreases binding of Shiga-like toxin-1B on human intestinal epithelial cell line HT29 stimulated with TNF-alpha and IL-1beta: suppression of p38, JNK and NF-kappaB p65 as potential targets. 1681 91


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