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)

Bradykinin (BK) is a potent neutrophil chemotractant, proinflammatory mediator, and angiogenic factor, which acts through G protein-coupled receptors (GPCRs). Here we studied the mechanisms involved in IL-8 generation by BK in human airway smooth muscle cells focusing on the transcription factors involved and role of endogenous prostanoids in transcription factor activation. Transfection experiments with wild-type IL-8 promoter constructs or constructs with NF-kappaB, AP-1, and NF-IL-6 binding site mutations suggested that all three transcription factors were necessary for optimal IL-8 expression. BK increased NF-kappaB, AP-1, and NF-IL-6 binding to the IL-8 promoter by electrophoretic mobility shift assay. NF-kappaB, the most important transcription factor in the current study, was translocated to the nucleus after BK stimulation. Indomethacin, a cyclooxygenase inhibitor, partially inhibited IL-8 release and the promoter binding of AP-1 and NF-IL-6, but not NF-kappaB. Furthermore, exogenous prostaglandin E2 stimulated AP-1 and NF-IL-6 binding to the IL-8 promoter. The anti-inflammatory glucocorticoid dexamethasone inhibited NF-kappaB translocation and the promoter binding of NF-kappaB, AP-1, and NF-IL-6. These results are the first to delineate the transcription factors involved in BK induced IL-8 release. Transcriptional activation of the IL-8 promoter by BK involves the prostanoid-independent activation of NF-kappaB, and prostanoid-dependent activation of AP-1 and NF-IL-6 plays a key role in augmenting the response. Endogenous prostanoid generation in response to GPCR ligands such as BK may be an important mechanism whereby GPCRs signal to the nucleus to maximize the transcription of inflammatory response genes.
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PMID:Transcriptional regulation of interleukin (IL)-8 by bradykinin in human airway smooth muscle cells involves prostanoid-dependent activation of AP-1 and nuclear factor (NF)-IL-6 and prostanoid-independent activation of NF-kappaB. 1274 73

Selected ester- (AL-5898 and AL-8417) and amide-linked benzopyran analogues (AL-7538 and AL-12615) were evaluated in vitro for their ability to inhibit key enzymes/processes of the inflammatory response. AL-7538 and AL-12615 exhibited weak intrinsic cyclooxygenase inhibitory activity (IC50 = 13 microM, 37 microM). In contrast, 5-HETE and LTB4 synthesis in A(23187)-stimulated neutrophils was effectively inhibited by both ester and amide analogs (IC50 = 2-3 microM). While there was some indication for differing sensitivities among benzopyran esters and amides in the suppression of cytokine synthesis in stimulated U-937 cells, there appeared to be no great discrimination when assessing their effect on U-937 cell adhesion to IL-1beta activated HMVEC-L cells. Inhibition of cell adhesion was concentration-dependent, with IC50 values ranging between 18 microM and 30 microM for AL-5898. Concentration-dependent inhibition of inflammatory cytokine production (i.e., IL-1beta, TNF-alpha, GM-CSF and IL-6) was also apparent in LPS-stimulated, cultured PBMC as well as in PMA/A(23187) activated U-937 cells monitoring the synthesis of IL-1beta, IL-8, TNF-alpha, and MCP-1. Notably, the hydrolysis products of the benzopyranyl ester, AL-5692 and (S)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid, were devoid of pharmacological activity when assessed for inhibition of monocyte adhesion or IL-1beta synthesis. Collectively, our data demonstrate the unique in vitro polypharmacology of a novel series of benzopyran analogs that suppress pivotal enzymes and processes in the inflammatory response.
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PMID:Characterization of the in vitro anti-inflammatory activity of AL-5898 and related benzopyranyl esters and amides. 1277 75

The metabolism of arachidonic acid through the cyclooxygenase pathway is a highly regulated cellular process that results in the formation of PGH2. This unstable intermediate can be enzymatically metabolized to PGE2 by the actions of a microsomal 17 kDa PGE synthase (mPGES1). Treatment of A549 cells with IL-1beta for 24 h resulted in a twofold increase in mPGES1 mRNA, protein expression, and PGES specific activity. To understand the relationship between expression of mPGES1 and PGE2 formation, IL-1beta treated cells were incubated with increasing concentrations of antisense oligonucleotides (ASO) and their effects compared to cells treated with reverse sense oligonucleotides (RSO) designed against the ATG translation initiation codon of mPGES1. Incubation with ASO resulted in a 44% reduction in mRNA expression level as compared to RSO-treated cells. Microsomal preparations isolated from ASO- and RSO-treated cells were analyzed for their ability to convert PGH2 to PGE2 in the presence 2.5 mM reduced glutathione. An approximate 50% reduction (ASO: 1.8 nmol/min/mg, RSO: 3.7 nmol/min/mg) in PGES activity, protein expression by immunodetection, and extracellular PGE2 release was detected in these samples. As a control in these studies, the protein levels of COX2 and secreted IL-8 were quantified; no change in these levels was observed. These results demonstrate the direct association between mPGES1 expression, its enzymatic activity, and total PGE2 production following an inflammatory stimulus.
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PMID:Inhibition of IL-1beta-dependent prostaglandin E2 release by antisense microsomal prostaglandin E synthase 1 oligonucleotides in A549 cells. 1289 May 77

The specific binding of transcription factors to DNA has been shown to be inhibited by chromatin structure and increased by cooperative interactions with other proteins. Consequently, in situ analysis using chromatin immunoprecipitation offers the most accurate view of transcriptional control. Transient transfection studies and in vitro analyses of IL-1-induced cox-2 transcription in a number of cell types have indicated regulation by either nuclear factor kappa B (NF-kappa B) or CCAAT/enhancer binding protein (C/EBP beta), or both acting cooperatively. To determine the mechanisms of COX-2 (cyclooxygenase or prostaglandin endoperoxide synthase) induction in cultured human myometrial cells in situ, we examined the cross-linking of the RelA subunit of NF-kappa B and C/EBP beta to the cox-2 promoter and flanking sequences. As a control, we inspected the interaction of these transcription factors with the IL-8 gene, which has been shown in other cell types to be activated by the cooperative interaction of NF-kappa B and C/EBP beta. Indeed, both transcription factors were cross-linked to the il-8 promoter after IL-1 treatment, but only RelA was cross-linked to cox-2 DNA. The il-8 promoter was also found to physically interact with proteins cross-linked to sites further upstream. IL-1 treatment also increased polymerase II cross-linking to both promoters and increased histone H4 acetylation at specific sites. These results indicate that modification of chromatin structure is part of the response to IL-1 stimulation. Chromatin immunoprecipitation thus provides critical insight into the mechanisms of COX-2 and IL-8 expression in human myometrial cells.
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PMID:In situ analysis of interleukin-1-induced transcription of cox-2 and il-8 in cultured human myometrial cells. 1464 17

Previously we reported that linoleic acid (LA), but not oleic acid, caused a marked increase in the secretion of IL-8 by Crohn's human intestinal smooth muscle (HISM) cells. Antioxidants inhibited this response, implicating a role for oxidative stress and NF-kappaB, a transcription factor for IL-8 that is activated by oxidative stress. In this study, we examined two mechanisms whereby LA, the dietary precursor for arachidonic acid (AA), could increase the production of IL-8 via activation of AA pathways: 1) by generation of reactive oxygen species by the AA-pathway enzymes to activate NF-kappaB or 2) by AA metabolites. Normal and Crohn's HISM cells were exposed to LA, oxidizing solution (Ox), or oxidizing solution enriched with LA (OxLA). Exposure of cells to Ox or OxLA induced oxidative stress as determined by thiobarbituric acid reactive substances. In normal cells, Ox but not LA activated NF-kappaB as determined by transfection experiments and Western blot. In Crohn's cells, NF-kappaB was spontaneously activated and was not further activated by Ox or LA. In contrast, TNF-alpha markedly increased activation of NF-kappaB in both normal and Crohn's cells. These results indicated that LA did not increase IL-8 by activating NF-kappaB, so we evaluated the second mechanism of an effect of AA metabolites. In normal cells, OxLA, but not LA, markedly stimulated IL-8, whereas in Crohn's cells, both OxLA and LA stimulated IL-8. OxLA, also stimulated production of AA metabolites leukotriene B(4) (LTB(4)), PGE(2), and thromboxane B(2) (TXB(2)) by normal and Crohn's cells. To determine whether AA metabolites mediated the IL-8 response, cells were treated with OxLA plus indomethacin (Indo), a cyclooxygenase inhibitor, and nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor. Both Indo and NDGA blocked the IL-8 response to OxLA. To determine more specifically a role for AA metabolites, AA was used. Similar to OxLA, OxAA stimulated production of IL-8 and AA metabolites. Pinane thromboxane, a selective thromboxane synthase inhibitor and receptor blocker, inhibited OxAA stimulation of TXB(2) and IL-8 in a dose-response manner. MK886, a selective 5-lipoxygenase inhibitor, inhibited OxAA stimulation of LTB(4) and IL-8 also in a dose-response manner. Analysis of specific gene products by RT-PCR demonstrated that HISM cells expressed receptors for both thromboxane and LTB(4). We conclude that AA metabolites mediated the IL-8 response to LA in HISM cells. Both cyclooxygenase and lipoxygenase pathways were involved. LA did not increase IL-8 by activating NF-kappaB, but NF-kappaB appeared to be involved, because LA increased IL-8 only in situations where NF-kappaB was activated, either spontaneously in Crohn's cells or by Ox in normal cells. We speculate that AA metabolites increased IL-8 production by enhancing NF-kappaB-dependent transcription of IL-8.
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PMID:Linoleic acid induces interleukin-8 production by Crohn's human intestinal smooth muscle cells via arachidonic acid metabolites. 1465 10

By means of semi-quantitative RT-PCR, expression of a number of immune relevant genes was studied in skin of small rainbow trout Oncorhynchus mykiss (Walbaum, 1792) fry during both primary and secondary infections with the ectoparasitic monogenean Gyrodactylus derjavini Mikailov, 1975. The target genes studied included the cyto- and chemokines TNF-alpha1, TNF-alpha2, TGF-beta and IL-8, the inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) genes and finally, two cell markers, the beta-chains of TCR and MHC II, from the adaptive arm of the immune system. In general, constitutive expression of all studied genes was apparent. Significant increases in expression of the TNF-alpha1 isoform could be observed at day 8 p.i. in primary infections and although less marked, the alpha2 isoform of TNF showed a similar trend. With the cytokine TGF-beta, 8-10 times increase in the transcription levels was observed in secondary infections compared to uninfected hosts. However, no parasite related changes in expression patterns could be observed for IL-8. Parasite infections elicited strong iNOS expression by 4 days p.i., but significant differences were not detected before day 8 p.i., when transcript levels were increased 5.5-9.6 times compared to uninfected controls. Augmented expression of COX-2 could also be observed in primary, but not secondary, infections at later stages of infections. No clear parasite related changes in transcript levels of the two cell markers TCRbeta and MHC IIbeta could be observed. Although the cellular source(s) was not determined, most of the examined factors appear to take part in a local signalling network of pivotal importance for the initiation, orchestration, effectuation and modulation of immune responses in rainbow trout against the ectoparasite G. derjavini.
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PMID:Expression of immune response genes in rainbow trout skin induced by Gyrodactylus derjavini infections. 1474 Nov 33

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

Elevated tumor cyclooxygenase (COX)-2 activity plays a multifaceted role in non-small cell lung cancer (NSCLC). To elucidate the role of COX-2 in the in vitro and in vivo expression of two known NSCLC angiogenic peptides, CXC ligand (CXCL) 8 and CXCL5, we studied two COX-2 gene-modified NSCLC cell lines, A549 and H157. COX-2 overexpression enhanced the in vitro expression of both CXCL8 and CXCL5. In contrast, specific COX-2 inhibition decreased the production of both peptides as well as nuclear translocation of nuclear factor kappaB. In a severe combined immunodeficient mouse model of human NSCLC, the enhanced tumor growth of COX-2-overexpressing tumors was inhibited by neutralizing anti-CXCL5 and anti-CXCL8 antisera. We conclude that COX-2 contributes to the progression of NSCLC tumorigenesis by enhancing the expression of angiogenic chemokines CXCL8 and CXCL5.
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PMID:Cyclooxygenase-2-dependent expression of angiogenic CXC chemokines ENA-78/CXC Ligand (CXCL) 5 and interleukin-8/CXCL8 in human non-small cell lung cancer. 1499 49

1. This study characterises some of the mechanisms and mediators involved in the orofacial nociception triggered by injection of formalin into the upper lip of the rat, by assessing the influence of various treatments on behavioural nociceptive responses (duration of facial rubbing) elicited either by a low subthreshold (i.e. non-nociceptive; 0.63%) or a higher concentration of the algogen (2.5%). 2. The kininase II inhibitor captopril (5 mg kg(-1), s.c.) and prostaglandin(PG) E(2) (100 ng lip(-1)) potentiated both phases of the response to 0.63% formalin, whereas tumour necrosis factor (TNF alpha; 5 pg lip(-1)), interleukin(IL)-1 beta (0.5 pg lip(-1)), IL-6 (2 ng lip(-1)) and IL-8 (200 pg lip(-1)), or the indirectly acting sympathomimetic drug tyramine (200 microg lip(-1)), each augmented only the second phase of nociception. 3. Conversely, both phases of nociception induced by 2.5% formalin were inhibited by the bradykinin (BK) B(2) receptor antagonist HOE140 (5 microg lip(-1)) or the selective beta(1)-adrenoceptor antagonist atenolol (100 microg lip(-1)). However, the BK B(1) receptor antagonist des-Arg(9)-Leu(8)-BK (1 and 2 microg lip(-1)), antibody and/or antiserum against each of the cytokines, the adrenergic neurone blocker guanethidine (30 mg kg(-1) day(-1), s.c., for 3 days) and the cyclooxygenase(COX)-2 inhibitor celecoxib (50 and 200 microg lip(-1), s.c.; or 1 and 3 mg kg(-1), i.p.) reduced only the second phase of the response. The nonselective COX inhibitor indomethacin and the 5-lipoxygenase activating protein inhibitor MK886 did not change formalin-induced nociception. 4. Our results indicate that BK, TNF-alpha, IL-1 beta, IL-6, IL-8, sympathetic amines and PGs (but not leukotrienes) contribute significantly to formalin-induced orofacial nociception in the rat and the response seems to be more susceptible to inhibition by B(2) receptor antagonist and selective COX-2 inhibitor than by B(1) receptor antagonist or nonselective COX inhibitor.
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PMID:Involvement of bradykinin, cytokines, sympathetic amines and prostaglandins in formalin-induced orofacial nociception in rats. 1500 4

IL-1 and IL-18 are members of the IL-1 family of ligands, and their receptors are members of the IL-1 receptor family. Although several biological properties overlap for these cytokines, differences exist. IL-18 uniquely induces IFN-gamma from T lymphocytes and natural killer cells but does not cause fever, whereas fever is a prominent characteristic of IL-1 in humans and animals. In the present study, human epithelial cells were stably transfected with the IL-18 receptor beta chain and responded to IL-18 with increased production of IL-1alpha, IL-6, and IL-8. Five minutes after exposure to either cytokine, phosphorylation of mitogen activated protein kinase (MAPK) p38 was present; specific inhibition of p38 MAPK reduced IL-18 activity to background levels. Whereas IL-1beta induced the expression of the NF-kappaB-reporter gene and was suppressed by competitive inhibition of NF-kappaB binding, IL-18 responses were weak or absent. In contrast to IL-1beta, IL-18 also did not activate degradation of the NF-kappaB inhibitor. After 4 h, both cytokines induced comparable levels of mRNA for the chemokine IL-8 but, in the same cells, steady-state levels of cyclooxygenase (COX)-2 mRNA were high after IL-1beta but low or absent after IL-18. After 30 h, IL-18-induced COX-2 appeared in part to be IL-1 dependent. Similarly, low levels of prostaglandin E2 were measured in IL-18-stimulated A549 cells and freshly obtained primary human monocytes and mouse macrophages. We conclude that in epithelial cells, IL-18 signal transduction is primarily via the MAPK p38 pathway rather than NF-kappaB, which may explain the absence of COX-2 and the failure of IL-18 to cause fever.
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PMID:Differences in signaling pathways by IL-1beta and IL-18. 1516 79


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