UNIPROT:P10145 - FACTA Search

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)

IL-8 is an important neutrophil and eosinophil chemoattractant in asthma. A recent report has suggested that bradykinin (BK), an asthmatic mediator, induces the release of IL-8 in nonairway cells. We have recently reported that BK causes cyclooxygenase (COX)-2 induction and PGE2 release in human airway smooth muscle (ASM) cells. In this study, we tested the ability of BK to induce IL-8 from these cells and explored the role of COX products and COX-2 induction in this process. Confluent serum-deprived human ASM cells were studied. IL-8 was assayed by specific ELISA. Unstimulated cells released low levels of IL-8. BK enhanced IL-8 release in a concentration- and time-dependent fashion (maximum 50-fold increase over basal). The nonselective COX inhibitor indomethacin and the selective COX-2 inhibitor NS-398 strongly inhibited BK-stimulated PGE2 and IL-8 production. The COX substrate arachidonic acid also caused PGE2 and IL-8 production, and its effect was inhibited by nonselective COX inhibitors but unaffected by NS-398. Both the BK- and arachidonic acid-induced IL-8 production was inhibited by the protein synthesis inhibitors cycloheximide and actinomycin D and by the steroid dexamethasone. Furthermore, exogenous PGE2 and calcium ionophore A23187 also stimulated IL-8 release. BK-induced IL-8 release was mimicked by the BK B2 receptor agonist (Tyr(Me)8)-BK and was potently inhibited by the selective B2 receptor antagonist HOE-140. These results suggest that human ASM can be a source of IL-8 and also that endogenous prostanoids, involving both COX-1 and COX-2, have a novel role in mediating BK-induced IL-8 production.
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PMID:Bradykinin stimulates IL-8 production in cultured human airway smooth muscle cells: role of cyclooxygenase products. 972 50

Nitric oxide (NO) donors are capable of ripening the human cervix during pregnancy. The purpose of this study was to examine how NO donors may be involved in this process. Cervical biopsies were obtained from pregnant women randomized to receive isosorbide mononitrate (n = 10) or no treatment (n = 10) prior to suction termination. Enzyme-linked immunosorbent assays (ELISA) were performed on culture supernatant for interleukin (IL)-1, IL-6, IL-8, IL-10, IL-15, tumour necrosis factor-alpha, monocyte chemoattractant protein-1 and prostaglandin metabolites. Immunohistochemistry was performed to localize these cytokines, cyclooxygenase (COX)-1, COX-2 and prostaglandin dehydrogenase in cervical tissue and reverse transcription-polymerase chain reaction (RT-PCR) to identify COX-1 and COX-2 expression. Biopsies treated with the NO donor isosorbide mononitrate (IMN) produced significantly greater amounts of prostaglandin F(2alpha) in culture and lower amounts of thromboxane B(2) than controls (572.8 versus 34.9 pg/ml, P < 0.05; 53.3 pg/ml versus 530.9 pg/ml, P < 0.01 respectively). The release of other prostaglandins and of cytokines was not affected by treatment with NO. Inflammatory mediators were localized to cervical tissue and COX-1 and COX-2 expression was confirmed by RT-PCR. In conclusion, the mechanism of NO donor-induced cervical ripening during pregnancy may be mediated in part via increased prostaglandin F(2alpha) synthesis.
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PMID:Nitric oxide donors stimulate prostaglandin F(2alpha) and inhibit thromboxane B(2) production in the human cervix during the first trimester of pregnancy. 1050 27

Increased production of prostaglandins and cytokines by amnion, particularly prostaglandin (PG) E2, interleukin (IL)-6 and IL-8, is thought to be an important event in infection-associated preterm labour. We characterized the amnion-derived AV3 cell line to determine its appropriateness as a model for investigation of the regulation of amnion cytokine and PG production. Amnion-derived AV3 cells were treated with tumour necrosis factor-alpha (TNF-alpha, interleukin-1beta (IL-1beta), epidermal growth factor (EGF) and phorbol 12-myristate 13-acetate (PMA) and IL-6, IL-8 and prostaglandin production was determined by immunoassay. Production of IL-6 and IL-8 rose dramatically with all treatments. PGE2, but not PGF2alpha or 6-keto-PGF1alpha, biosynthesis was also increased in a concentration-dependent manner with all treatments. A rapid increase in PGHS-2 (but not PGHS-1) mRNA expression was observed in response to TNF-alpha and IL-1beta. We conclude that the AV3 cell line inflammatory response profile is similar to those observed in primary amnion and other amnion-derived cell lines, and is an appropriate model for human amnion.
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PMID:Characterization of the amnion-derived AV3 cell line for use as a model for investigation of prostaglandin-cytokine interactions in human amnion. 1071 11

Colorectal cancers (CRCs) are one of the most common forms of cancer in Poland and one of the leading causes of death. The tumors have been attributed to genetic, dietary, and other environmental factors, but recently growth factors such as gastrin have also been implicated in the carcinogenesis. The relationship between plasma amidated and nonamidated gastrin in CRCs is controversial. This study was designed (1) to determine the plasma levels of progastrin and amidated gastrin in 50 CRC patients before and 3-6 months after removal of the tumor, (2) to determine the tumor concentrations of these gastrin peptides and the level of expression for gastrin mRNA and gastrin/CCK(B) receptor mRNA, (3) to examine the expression of cyclooxygenase COX-1 and COX-2 mRNA in CRC tissue, and (4) to compare the prevalence of Hp and its cytotoxic protein, CagA, and cytokines (TNFalpha, IL-1beta, and IL-8) in CRCs, before and after removal of tumor. It was found that the CRC, its resection margin, and the plasma contained severalfold higher levels of progastrin than of amidated gastrins and that the removal of the CRC tumor resulted in a marked reduction in plasma progastrin level without a significant alteration in plasma levels of amidated gastrins. Both gastrin and CCK(B)-R mRNA were detected in the cancer tissue and resection margin by RT-PCR, and similarly, COX-1 and COX-2 mRNA were expressed in these tissues of most CRCs. The seroprevalence of Hp, especially that expressing CagA, and levels of IL-1beta, but not other cytokines, were significantly higher in CRC patients than in 100 age-, gender-, and profession-matched controls and did not change significantly about 3-6 months after tumor resection. We conclude that (1) the CRC and its margin contain large amounts of progastrin and show gene expression of gastrin, CCK(B)-R, and COX-2; (2) removal of the CRC markedly reduces the plasma concentrations of progastrin; (3) the Hp infection rate is higher in CRC, and this may contribute to colorectal cancerogenesis via enhancement of progastrin and gastrin release; and (4) plasma progastrin concentrations might serve as a biomarker of CRC.
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PMID:Progastrin and cyclooxygenase-2 in colorectal cancer. 1235 42

Glomerular mesangial cells (GMC) exert an essential maintaining effect on hemodynamic integrity and immune competence of the kidney through arachidonate metabolism. To clarify this, cultured rat GMC were measured for the expression and production of cyclooxygenase (COX) and excretion of prostaglandin (PG). The rat GMC spontaneously expressed type 1 cyclooxygenase (COX-1), but not COX-2. The PGE2 and thromboxane B2 (TXB2) were spontaneously produced by the cells. Interleukin (IL)-1beta (25 ng/ml), IL-8 (25 ng/ml), growth-related oncogene-alpha (GRO, 50 ng/ml) and tumor necrosis factor-alpha (TNF-alpha, 25 ng/ml) stimulated the COX-1 protein production as demonstrated by Western blot and enhanced PGE2 synthesis in GMC, beginning on 2 h of incubation, and steadily enhanced TXB2 synthesis over a 24-h period. Lipopolysaccharide (LPS, 100 ng/ml) enhanced both PGE2 and TXB2 syntheses from 2 h to at least 24 h of incubation. Collectively, the proinflammatory cytokines could enhance COX-1 but not COX-2 expression in GMC leading to increased PGE2 and TXB2 production. These biochemical events may be implicated in normal renal physiology as well as in pathogenesis of glomerular diseases.
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PMID:Proinflammatory cytokines enhance COX-1 gene expression in cultured rat glomerular mesangial cells. 1497 59

Prostaglandin E synthase (PGES) including isoenzymes of membrane-associated PGES (mPGES)-1, mPGES-2, and cytosolic PGES (cPGES) is the recently identified terminal enzyme of the arachidonic acid cascade. PGES converts prostaglandin (PG)H2 to PGE2 downstream of cyclooxygenase (COX). We investigated the expression of PGES isoenzyme in articular chondrocytes from patients with osteoarthritis (OA). Chondrocytes were treated with various cytokines and the expression of PGES isoenzyme mRNA was analyzed by the reverse transcription-polymerase chain reaction and Northern blotting, whereas Western blotting was performed for protein expression. The subcellular localization of mPGES-1 was determined by immunofluorescent microscopy. Conversion of arachidonic acid or PGH2 to PGE2 was measured by enzyme-linked immunosorbent assay. Finally, the expression of mPGES-1 protein in OA articular cartilage was assessed by immunohistochemistry. Expression of mPGES-1 mRNA in chondrocytes was significantly induced by interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha, whereas other cytokines, such as IL-4, IL-6, IL-8, IL-10, and interferon-gamma, had no effect. COX-2 was also induced under the same conditions, although its pattern of expression was different. Expression of cPGES, mPGES-2, and COX-1 mRNA was not affected by IL-1beta or TNF-alpha. The subcellular localization of mPGES-1 and COX-2 almost overlapped in the perinuclear region. In comparison with 6-keto-PGF1alpha and thromboxane B2, the production of PGE2 was greater after chondrocytes were stimulated by IL-1beta or TNF-alpha. Conversion of PGH2 to PGE2 (PGES activity) was significantly increased in the lysate from IL-1beta-stimulated chondrocytes and it was inhibited by MK-886, which has an inhibitory effect on mPGES-1 activity. Chondrocytes in articular cartilage from patients with OA showed positive immunostaining for mPGES-1. These results suggest that mPGES-1 might be important in the pathogenesis of OA. It might also be a potential new target for therapeutic strategies that specifically modulate PGE2 synthesis in patients with OA.
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PMID:Membrane-associated prostaglandin E synthase-1 is upregulated by proinflammatory cytokines in chondrocytes from patients with osteoarthritis. 1522 71

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

Licochalcone A, a novel flavonoid isolated from the root of Glycyrrhiza inflata, has been reported to exhibit anti-inflammatory activity in animal models. In this study, we examined the effect of licochalcone A on the production of chemical mediators such as prostaglandin (PG)E2 and cytokines by interleukin (IL)-1beta in human skin fibroblasts. Licochalcone A (IC50 15.0 nM) inhibited PGE2 production, but not IL-6 and IL-8 production, in response to IL-1beta. NS-398 (IC50 1.6 nM), a COX-2 selective inhibitor, also suppressed the PGE2 production. Furthermore, licochalcone A and NS-398 suppressed PGF(2alpha) production by IL-1beta. However, licochalcone A (1 microM) had no effect on increased levels of cyclooxygenase (COX)-2 mRNA and protein in cells. Dexamethasone (100 nM) not only inhibited PGE2, PGF(2alpha), IL-6 and IL-8 production but also strongly suppressed the expression of COX-2 mRNA and protein. Licochalcone A had no effect on COX-1-dependent PGE2 production, whereas indometacin (100 nM), a dual inhibitor of COX-1 and COX-2, was very effective. These results suggest that licochalcone A induces an anti-inflammatory effect through the inhibition of COX-2-dependent PGE2 production. Furthermore, it appears that the inhibitory effect of licochalcone A on PGE2 production in response to IL-1beta is quite different from that of the steroid.
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PMID:Inhibition by licochalcone A, a novel flavonoid isolated from liquorice root, of IL-1beta-induced PGE2 production in human skin fibroblasts. 1635 11

The objective of the present study was to determine the influence of cyclooxygenase-2 (COX-2) inhibition by Celecoxib (CLX) in humans with distal colorectal adenocarcinoma (CRC) on serum and tumor levels of progastrin and gastrin and serum levels of proinflammatory cytokines (IL-8, TNF-alpha). In addition, the effects of this CLX treatment on tumor and adjacent mucosa expression of gastrin, its receptors (CCK2), and COX-1 and COX-2, as well as protein expression of the active form of nuclear factor kappa B (NFkappa B) and the apoptotic-related proteins Bcl-2 and survivin, have been examined. Ten distal CRC patients were examined twice, once before and then after 14-day treatment with CLX (200 mg bid). Large biopsy samples were taken from the tumor and intact mucosa 10 cm above the tumor. For comparison, 20 age- and sex-matched healthy controls were enrolled and treated with CLX as CRC patients. Serum levels of IL-8 and TNF-alpha were measured by enzyme-linked immunosorbent assay, and serum levels of amidated gastrins and progastrin, by specific radioimmunoassay. The gene or protein expressions of progastrin, gastrin, CCK2, COX-1, COX-2, Bcl-2, and survivin as well as NFkappa B were determined by RT-PCR or Western blot in biopsy samples of tumor and intact mucosa of CRC patients. Serum IL-8 and TNF-alpha values were severalfold higher in CRC patients than in controls. The increase in serum proinflammatory cytokines was accompanied by increased expression of the active form of NFkappa B. Serum progastrin levels were also found to be significantly higher in CRC than in controls. Treatment of CRC with CLX resulted in a significant decrease in serum levels of progastrin and this was accompanied by an increment in tumor expression of COX-2 with a concomitant reduction in gastrin, Bcl-2, survivin, and NFkappa B expression. We conclude that (1) distal CRC patients show significantly higher serum progastrin levels than matched healthy controls, confirming that this hormone may be implicated in rectal carcinogenesis; (2) CRC patients exhibit significantly higher serum levels of IL-8 and TNF-alpha than healthy controls, probably reflecting more widespread inflammatory reaction in the colonic mucosa in CRC; (3) gastrin, COX-2, Bcl-2, survivin, and NFkappa B were overexpressed in CRC tumor compared to intact mucosa, but treatment with CLX significantly reduced serum levels of progastrin and IL-8 and TNF-alpha, which could mediate the up-regulation of COX-2 in CRC; and (4) CLX also enhanced expression of COX-2, while inhibiting the expression of gastrin, Bcl-2, survivin, and NFkappa B, suggesting that COX-2 inhibition might be useful in chemoprevention against CRC, possibly due to suppression of the antiapoptotic proteins and reduction in progastrin-induced and NFkappa B-promoted tumor growth.
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PMID:Effects of cyclooxygenase-2 inhibition on serum and tumor gastrins and expression of apoptosis-related proteins in colorectal cancer. 1661 3

Tetrandrine (TET), a bis-benzylisoquinoline alkaloid isolated from the dried root of hang-fang-chi (Stephania tetrandra S. Moore), is traditionally used in China for treating inflammation, hypertension and silicosis. In this study, our aim was to examine the anti-inflammatory mechanism of TET through measuring the inducible nitric oxide synthase (iNOS), cyclooxygenase-1, and -2 (COX-1 and COX-2) expression, cytokines (TNF-alpha, IL-4 and IL-8) formation, nitric oxide (NO) release and prostaglandin E2 (PGE2) generation in lipopolysaccharide (LPS)-induced human monocytic (THP-1) cells. Results showed that TET remarkably suppressed the LPS (1 microg/ml) induction of NO release and PGE2 generation. It also significantly attenuated the LPS-induced transcription of proinflammatory cytokines (TNF-alpha, IL-4 and IL-8) in a dose-dependent manner. Furthermore, TET at 100 microM significantly blocked the LPS induction of iNOS and COX-2 expression, but not the COX-1. Taken together, these results suggest that TET exerts anti-inflammatory effects probably through the suppression of COX-2 and iNOS expression.
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PMID:Tetrandrine inhibits proinflammatory cytokines, iNOS and COX-2 expression in human monocytic cells. 1720 60

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