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)

Previous studies suggest that antagonists of cyclooxygenases 1 and 2 (COX-1, -2) inhibit angiogenesis in tumor xenografts, but the molecular mechanisms involved remain unclear. Here we characterized the effects of non-selective (indomethacin) and selective (NS398, celecoxib) cyclooxygenase inhibitors on parameters of angiogenesis in human pancreatic adenocarcinoma cells. COX-1 expression was constitutive in 9/9 pancreatic cancer cell lines, whereas COX-2 and cytosolic phospholipase A2 (cPLA2) expression were observed in 4/9 cell lines (BxPC3, Capan2, Cfpac1, and L3.6 pl). Production of the COX product, prostaglandin E2, correlated with expression of cPLA2 and COX-2 and was blocked by non-steroidal anti-inflammatory drugs (NSAIDs, indomethacin or NS398). In contrast to the findings of others, neither indomethacin nor NS398 affected tumor cell secretion of angiogenic factors (VEGF, bFGF, IL-8) at concentrations that produced maximal inhibition of PGE2 production, and higher concentrations increased angiogenic factor production. We also studied the effects of celecoxib in orthotopic L3.6 pl xenografts. Immunofluorescence analyses revealed high-level expression of COX-2 in endothelial cells in L3.6 pl xenografts that increased following therapy with celecoxib, whereas the tumor cells expressed uniformly low levels of COX-2. Celecoxib did not decrease tumor-associated VEGF levels in orthotopic human L3.6 pl xenografts, but the drug did decrease tumor microvessel density (MVD) and increase apoptosis in tumor-associated endothelial cells in a dose-dependent fashion. Together, our results demonstrate that the anti-angiogeneic effects of NSAIDs in human pancreatic cancer cells are exerted via direct effects on endothelial cells.
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PMID:Celecoxib inhibits angiogenesis by inducing endothelial cell apoptosis in human pancreatic tumor xenografts. 1547 58

The population of Linxian in north central China is at high risk for gastric cardia adenocarcinoma (GCC) and esophageal squamous cell carcinoma (ESCC), and chronic inflammation may contribute to this risk. Interleukin-8 (IL8), a potent chemoattractant, has three well-characterized single nucleotide polymorphisms (SNP), one (-251) of which alters transcriptional activity. Four well-described SNPs in the two IL8 receptors, IL8RA and IL8RB, have been associated with inflammation. We conducted a case-cohort study in the Nutrition Intervention Trials (Linxian, China) to assess the association between these SNPs and incident GCC (n = 90) and ESCC (n = 131). IL8, IL8RA, and IL8RB SNPs were analyzed using a multiplex assay system, haplotypes were constructed, and risks were estimated using Cox proportional hazards models. The homozygous variants of IL8 -251 and +396 were associated with 2-fold increased relative risks for GCC, but the highest risk observed was for the AGT/AGC haplotype of IL8 -251/+396/+781 (relative risk, 4.14; 95% confidence interval, 1.31-13.1). Variation within IL8 was not associated with ESCC. Few subjects had variation at the IL8RA SNP and no significant associations were observed for IL8RB SNPs or haplotypes with either GCC or ESCC. We conclude that variation in IL8 seems to increase the risk for GCC but not ESCC in this high-risk population. These variants could confer an altered IL8 expression pattern or interact with environmental factors to increase the risk for inflammation and GCC.
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PMID:Variants of the IL8 and IL8RB genes and risk for gastric cardia adenocarcinoma and esophageal squamous cell carcinoma. 1559 88

We have demonstrated recently that PTHrP is upregulated in pancreatic adenocarcinoma and that the ECM exerts regulatory control, at least in part, over PTHrP expression. In our present study, we examined the potential signaling interactions between these 2 pathways. Our results demonstrate that, under serum-free conditions, adhesion of FG pancreatic adenocarcinoma cells on Fn is mediated by the alpha5beta1 integrin, whereas adhesion to Type I collagen is mediated by the alpha2beta1 integrin. alpha5beta1 integrin-mediated adhesion to Fn results in a phenotype that includes a reduction in cell proliferation, increased E-cadherin localization in cell-cell contacts, increased beta-catenin localization throughout the cell, inhibition of haptokinetic cell migration, and increased expression of PTHrP, IL-6 and IL-8 relative to alpha2beta1 integrin-mediated adhesion on Type I collagen. A phosphoprotein immunoblotting screen of FG pancreatic cancer cells grown on either Fn or Type I collagen indicates that GSK3 and PKB/Akt are differentially phosphorylated on these 2 substrates. These results implicate GSK3 and PKB/Akt in the integrin-mediated regulation of PTHrP, IL-6 and IL-8 in pancreatic cancer.
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PMID:GSK3 and PKB/Akt are associated with integrin-mediated regulation of PTHrP, IL-6 and IL-8 expression in FG pancreatic cancer cells. 1560 21

We previously designed and synthesized the new nuclear factor kappaB (NF-kappaB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of the antibiotic epoxyquinomicin C. We looked into the effect of DHMEQ on cellular phenotypes and tumor growth in mice injected with human breast carcinoma cell line MDA-MB-231 or MCF-7. In estrogen-independent breast adenocarcinoma cell line MDA-MB-231, NF-kappaB is constitutively activated. The addition of DHMEQ (10 microg/mL) completely inhibited the activated NF-kappaB for at least 8 hours. On the other hand, NF-kappaB is not activated in estrogen-dependent MCF-7 cells. In this cell line, DHMEQ completely inhibited the tumor necrosis factor-alpha-induced activation of NF-kappaB. DHMEQ did not inhibit the degradation of IkappaB but inhibited the nuclear translocation of NF-kappaB by both p65/p50 and RelB/p52 pathways. MDA-MB-231 cells secrete interleukin (IL)-6 and IL-8 without stimulation, and DHMEQ decreased the secretion levels of both cytokines. When MDA-MB-231 or MCF-7 cells were stimulated by tumor necrosis factor-alpha, the inhibitory effects of DHMEQ were still maintained. I.p. administration of DHMEQ (thrice a week) significantly inhibited the tumor growth of MDA-MB-231 (12 mg/kg) or MCF-7 (4 mg/kg) in severe combined immunodeficiency mice. No toxicity was observed during the experiment, including the loss of body weight. An immunohistological study on resected MCF-7 tumors showed that DHMEQ inhibited angiogenesis and promoted apoptosis. Furthermore, in Adriamycin-resistant MCF-7 cells highly expressing multidrug resistance gene-1, DHMEQ also exhibited the above capability, including down-regulation of IL-8. Thus, DHMEQ might be a potent drug for the treatment of various breast carcinomas by inhibiting the NF-kappaB activity.
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PMID:Targeting of nuclear factor kappaB Pathways by dehydroxymethylepoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo. 1570

We have studied the effect of sodium acetate exposure on the viability and proliferative activity of cultured human gastric adenocarcinoma epithelial (AGS) cells and changes in the release of proinflammatory cytokines. We evaluated the levels of IL-6, TNF-alpha, IL-8, and IL-1beta in cell culture supernatants using enzyme-linked immunosorbent assays, and cytokine mRNA levels were measured in whole cells using reverse transcriptase-polymerase chain reaction. We also measured cytokine levels in mice using immunohistochemistry. In vitro studies demonstrated that incubation with sodium acetate (up to 12.5 mM) for 72 h stimulated AGS cell viability and proliferation in a dose-dependent manner; however, incubation with >12.5 mM sodium acetate inhibited cell growth, also in a dose-dependent manner (the largest decrease in viability was >50%). Incubation with sodium acetate for 24 h increased the levels of IL-1beta, IL-8, and TNF-alpha protein and mRNAs (IL-6 was detected but its mRNA was not). The effect of sodium acetate on the expression of these cytokines in cell culture was verified in mice. Our data suggest that ingestion of high concentrations of sodium acetate in food has cytotoxic effects.
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PMID:Effect of sodium acetate on cell proliferation and induction of proinflammatory cytokines: a preliminary evaluation. 1600 58

Interleukin-8 (IL-8) is an angiogenic factor that promotes growth of pancreatic tumors. The purpose of this study was to determine if c-Src, a protein tyrosine kinase frequently overexpressed in pancreatic cancer, regulated IL-8 expression and to elucidate the Src-mediated signaling pathways that contribute to angiogenesis in pancreatic adenocarcinoma cells. In a panel of pancreatic cancer cell lines, expression of total and activated Src correlated with IL-8 production. Furthermore, ectopic expression of activated Src in PANC-1 cells with low endogenous Src activity significantly increased IL-8 production (P < 0.005). In contrast, pharmacologic inhibition of endogenous c-Src kinase activity or small interfering RNA-mediated "knockdown" of c-Src expression in L3.6pl cells with high Src expression and activity caused significant decreases in IL-8 production (P < 0.005). Inhibition of c-Src activity resulted in decreased phosphorylation of Akt, p38, and extracellular signal-regulated kinase (Erk)-1/2. Significant (P < 0.005) dose-dependent decreases were observed in IL-8 expression by inhibiting Src-dependent signaling molecules Erk-1/2 and p38 but not phosphatidylinositol 3-kinase. To assess the relevance of Src inhibition to angiogenesis, in vivo gelfoam assays were done. Robust infiltration of vessels was observed in gelfoam saturated with conditioned medium from pancreatic carcinoma cells. This angiogenesis was nearly abrogated in gelfoams saturated with conditioned medium from cells treated with the Src family kinase inhibitor, PP2 (P < 0.001). Thus, c-Src regulates critical "downstream" signaling pathways that contribute to expression of IL-8 in human pancreatic tumor cells, suggesting c-Src may be a target for therapeutic intervention in pancreatic adenocarcinoma.
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PMID:Expression and activity of SRC regulate interleukin-8 expression in pancreatic adenocarcinoma cells: implications for angiogenesis. 1610 72

A major component in green tea, epigallocatechin-3-gallate (EGCG), is reported to interfere with different steps of a number of inflammatory pathways. After oral administration, EGCG is retained in the gastrointestinal tract, where it is thought to exert preventive functions against inflammatory bowel disease and colon cancer. In this study, the human colon adenocarcinoma cell lines HT29 and T84 were used to investigate the effect of EGCG on intestinal inflammation. HT29 and T84 cells were stimulated with tumor necrosis factor (TNF)-alpha to induce the inflammatory condition and to trigger the inflammatory cascade in vitro and treated with EGCG to study its effect on inflammatory processes. The secretion of the chemokines interleukin (IL)-8, macrophage inflammatory protein (MIP)-3alpha, and prostaglandin E2 (PGE2) was determined by enzyme-linked immunosorbent assay. The gene expression level was measured by quantitative real-time polymerase chain reaction. Treatment of TNF-alpha-stimulated HT29 cells with EGCG dose-dependently inhibited the synthesis of IL-8, MIP-3alpha, and PGE2. Treatment with EGCG also inhibited the production of IL-8 and MIP-3alpha in TNF-alpha-stimulated T84 cells. Gene expression analysis in both HT29 and T84 cells revealed that EGCG down-regulates genes involved in inflammatory pathways. This study shows that EGCG acts broadly on the production of chemokines and PGE2 in the chemokine and eicosanoid pathways of colon epithelial cells. Therefore, EGCG might prove useful for the prevention and/or attenuation of colonic disorders.
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PMID:Epigallocatechin-3-gallate impairs chemokine production in human colon epithelial cell lines. 1612 9

Bone is a common site of cancer metastasis. Breast, prostate, and lung cancers show a predilection to metastasize to bone. Recently, we reported that the chemokine interleukin 8 (IL-8) stimulates both human osteoclast formation and bone resorption. IL-8 mRNA expression was surveyed in a panel of human breast cancer lines MDA-MET, MDA-MB-231, MDA-MB-435, MCF-7, T47D, and ZR-75, and the human lung adenocarcinoma cell line A549. IL-8 mRNA expression was higher in cell lines with higher osteolytic potential in vivo. Human osteoclast formation was increased by MDA-MET or A549 cell-conditioned medium, but not by MDA-MB-231. Pharmacologic doses of receptor activator of nuclear factor-kappaB (RANK)-Fc or osteoprotogerin had no effect on the pro-osteoclastogenic activity of the conditioned medium; however, osteoclast formation stimulated by conditioned medium was inhibited 60% by an IL-8-specific neutralizing antibody. The data support a model in which tumor cells cause osteolytic bone destruction independently of the RANK ligand (RANKL) pathway. Tumor-produced IL-8 is a major contributor to this process. The role of secreted IL-8 isoforms was examined by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, which detected distinct IL-8 isoforms secreted by MDA-MET and MDA-231 cells, suggesting different pro-osteoclastogenic activities of the two IL-8-derived peptides. These data indicate that (a) osteoclast formation induced by MDA-MET breast cancer cells and A549 adenocarcinoma cells is primarily mediated by IL-8, (b) cell-specific isoforms of IL-8 with distinct osteoclastogenic activities are produced by tumor cells, and (c) tumor cells that support osteoclast formation independent of RANKL secrete other pro-osteoclastogenic factors in addition to IL-8.
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PMID:Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway. 1632 49

CD43 is a heavily O-glycosylated type I trans-membrane protein, expressed at high levels on the surface of leukocytes. It is frequently overexpressed in early colon adenomas, but not in normal colon epithelial cells. To identify CD43 target genes, gene array analysis was performed using a tetracycline-inducible CD43 expression system in human colon adenocarcinoma SW480 cells. CD43 was demonstrated to down-regulate a variety of chemokine genes. Overexpression of CD43 suppressed constitutive as well as PMA-induced NF-kappaB activation and reduced the DNA binding of transcription factor p65 but not p50. Furthermore, a reduced NF-kappaB responsive promoter activity was observed and a decreased expression of proinflammatory chemokines MCP-1, IL-8 and GRO-alpha. These results suggest that overexpression of CD43 suppresses a subset of NF-kappaB target genes, partly via the inhibition of p65 transcriptional activity.
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PMID:Inhibition of NF-kappaB activation and chemokine expression by the leukocyte glycoprotein, CD43, in colon cancer cells. 1646 75

To investigate the effect of sodium nitrite on the viability of the human gastric adenocarcinoma epithelial cell line, AGS, cultured AGS cells were exposed to various concentrations of sodium nitrite for 24, 48 or 72 h. The cytotoxic response was assessed using a cell proliferation assay, and the extent of the response was evaluated on the basis of intracellular and extracellular levels of interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), interleukin 8 (IL-8) and tumor necrosis factor (TNF-alpha). Both mRNA and protein levels were measured for each cytokine. Sodium nitrite had a significant effect on AGS cell proliferation after a 72-h exposure. At low sodium nitrite concentrations (up to 6.25 mM), cell proliferation increased in a dose-dependent manner; however, exposure to higher concentrations resulted in a dose-dependent decrease in cell proliferation. Sodium nitrite at a low concentration (6.25 mM) increased IL-8 release, whereas IL-1 beta, IL-6, and TNF-alpha release increased only after exposure to high sodium nitrite concentration (25 mM). Our data demonstrate that sodium nitrite can induce the release of these inflammatory cytokines and that high concentrations of sodium nitrite decrease AGS cell proliferation.
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PMID:Sodium nitrite-induced cytotoxicity in cultured human gastric epithelial cells. 1658 Dec 24


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