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 monocytes (M phi) require stimulation with substances such as bacterial endotoxin [LPS (lipopolysaccharide)] to produce angiogenic activity. In this study, we report that stimulation of M phi with LPS (5 micrograms/ml) in the absence of L-arginine greatly reduced their production of angiogenic activity, as assessed in vivo in rat corneas and in vitro by chemotaxis of human umbilical vein endothelial cells (HU-VECs). D-Arginine did not substitute for L-arginine in the production of angiogenic activity. The nitric oxide synthase (NO synthase, EC 1.14-13.39) inhibitors NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME) both inhibited the production of angiogenic activity by LPS-stimulated M phi in the presence of L-arginine, suggesting the involvement of this enzyme in the pathway that generates angiogenic activity. Neither of these substances directly inhibited the M phi-derived angiogenic activity. LPS-induced production of the cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 8 (IL-8) was not significantly reduced when M phi were incubated in the absence of L-arginine. Similarly, L-NMMA and L-NAME did not significantly reduce the LPS-induced production of these cytokines by M phi in the presence of L-arginine. These results suggest that the LPS-stimulation-dependent generation of angiogenic activity by M phi requires an L-arginine-dependent NO-synthase effector mechanism that may be independent of the generation of TNF-alpha and IL-8.
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PMID:Production of angiogenic activity by human monocytes requires an L-arginine/nitric oxide-synthase-dependent effector mechanism. 751 98

The effect of cytokines, growth factors, mitogens, and bacterial products on nitric oxide (NO) generation by monolayers of small intestinal epithelial cells-6 (IEC-6) cells was evaluated. Subconfluent IEC-6 cells were maintained in DMEM containing 5% fetal calf serum and after 16-24 hr of incubation, the medium was replaced with fresh medium in the presence or absence of calcium ionophore (CaI), L-NAME, L-NNA, individual growth factors, cytokines, or mitogens. After 72 hr of culture, the media supernatant was collected and NO chi generation was determined. NO synthase activity was determined in sonicated supernatants of IEC-6 cells by [14C] arginine conversion to citrulline. NO chi generation in subconfluent cultures was greater than in fully confluent cultures, suggesting contact inhibition. NO chi generation by IEC-6 cells was significantly increased by CaI and inhibited by L-NAME and L-NNA. LPS, IL-1 beta, IL-2, IL-8, IFN-8, TFN-alpha, EGF, TGF-alpha, bFGF, and PHA significantly increased NO chi generation. NO synthase activity in IEC-6 cells (4.2 +/- 1.7 pmol/min/10(6) cells) was NADPH dependent. These results suggest that stimulation of NO chi generation by intestinal epithelial cells through cytokine bacterial products and mitogens may be one of the mechanisms responsible for their effects in the intestinal tract.
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PMID:NO chi generation by cultured small intestinal epithelial cells. 755 34

The regulatory signals required to induce the production of IL-8, an important neutrophil chemoattractant and activator, have yet to be clearly defined. We examined the role of nitric oxide (NO) in IL-8 regulation. The NO synthase inhibitor, (L)-NG-nitroarginine methyl ester (L-NAME), inhibited the TNF-stimulated IL-8 production in the human endothelial cell line, ECV304, in a dose-dependent manner without affecting cellular viability (TNF alone, 5.5 +/- 0.9 ng/ml; TNF + 5 mM L-NAME, 2.4 +/- 0.5 ng/ml). Moreover, exogenously added NO produced by the spontaneous NO generating compounds, S-Nitroso-N-acetyl-D,L-pennicillamine (SNAP) and Ethanamine, 2,2'-(hydroxynitrosohydrazono)bis- (DETA NONOate), induced a dose-dependent release of IL-8 from these cells. Maximal stimulation of IL-8 was found to be 1.2 +/- 0.1 ng/ml with the 1 mM concentration of SNAP and 1.6 +/- 0.1 ng/ml with the 2 mM concentration of DETA NONOate. These results provide key evidence substantiating a regulatory role of NO in IL-8 expression.
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PMID:Nitric oxide regulation of IL-8 expression in human endothelial cells. 779 82

Nitric oxide synthase (NOS) isoenzymes generate nitric oxide (NO), a sensitive multifunctional intercellular signal molecule. High NO levels are produced by an inducible NOS (iNOS) in activated macrophages in response to proinflammatory agents, many of which also regulate local bone metabolism. NO is a potent inhibitor of osteoclast bone resorption, whereas inhibitors of NOS promote bone resorption both in vitro and in vivo. The possibility that osteoclasts, like macrophages, express a regulated iNOS and produce NO as a potential autocrine signal following inflammatory stimulation was investigated in well-characterized avian marrow-derived osteoclast-like cells. NO production (reflected by medium nitrite levels) was markedly elevated in these cells by the proinflammatory agents lipopolysaccharide (LPS) and the synergistic action of IL-1 alpha, TNF alpha, and IFN gama. inhibitors of NOS activity (aminoguanidine, L-NAME) or iNOS induction (dexamethasone, TGF beta) reduced LPS-stimulated nitrite production. LPS also increased the NOS-associated diaphorase activity of these cells and their reactivity with anti-iNOS antibodies. RT-PCR cloning, using avian osteoclast-like cell RNA and human iNOS primers, yielded a novel 900 bp cDNA with high sequence homology (76%) to human, rat, and mouse iNOS genes. In probing osteoclast-like cell RNA with the PCR-derived iNOS cDNA, a 4.8 kb mRNA species was detected whose levels were greatly increased by LPS. Induction of iNOS mRNA by LPS, or by proinflammatory cytokines, occurred prior to the rise of medium nitrite in time course studies and was diminished by dexamethasone. Moreover, osteoclast-like cells demonstrated an upregulation of NO production and iNOS mRNA by IL-8 and IL-10, regulatory mechanism's not previously described. It is concluded that osteoclast-like cells express a novel iNOS that is upregulated by inflammatory mediators, leading to NO production. Therefore, NO may serve as both a paracrine and autocrine signal for modulating osteoclast bone resorption.
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PMID:Proinflammatory agents, IL-8 and IL-10, upregulate inducible nitric oxide synthase expression and nitric oxide production in avian osteoclast-like cells. 870 87

While the regulation of nitric oxide (NO) by inflammatory cytokines or lipopolysaccharide (LPS) has received considerable attention, NO modulation of cytokine expression has yet to be fully explored. The NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited interleukin (IL)-8 and IL-6 production in LPS-stimulated human whole blood in a dose-dependent manner. In the presence of 1 microgram/mL LPS, L-NAME blocked IL-8 release (72 +/- 4% inhibition at 20 mM (mean +/- SEM, p < .05)) 24 h post-LPS without affecting cellular viability. IL-6 production was significantly inhibited only with the highest dose of L-NAME used. L-NAME inhibition of IL-8 production was also observed at the mRNA level. Conversely, direct exposure of whole blood to NO with the spontaneous NO liberator DETA NONOate caused a dose-dependent stimulation of IL-8, but had no effect on IL-6 release. IL-8 concentrations rose from 8.3 +/- 1.9 ng/mL at 24 h to 31.7 +/- 7.6 ng/mL at 72 h with a single stimulation of 10 mM DETA NONOate. The hydroxyl radical scavenger dimethyl sulfoxide (DMSO) prevented the DETA NONOate induction of IL-8, suggesting the participation of the hydroxyl radical in the NO-induced IL-8 production. These results provide important evidence substantiating a role for NO as a regulator of cytokine expression.
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PMID:Nitric oxide regulation of interleukin-8 gene expression. 898 33

Recent evidence indicates that free oxygen radicals, in particular hydroxyl radicals, may act as intracellular second messengers for the induction of IL-8, a potent chemoattractant and activator of neutrophil granulocytes. Here we report that peroxynitrite (ONOO-), formed by a reaction of nitric oxide (NO) with superoxide, mediates IL-8 gene expression and IL-8 production in LPS-stimulated human whole blood. The NO synthase inhibitors aminoguanidine and NG-nitro-L-arginine methyl ester (L-NAME) blocked IL-8 release by approximately 90% in response to LPS (1 microg/ml), but did not affect the production of IL-1beta or TNF-alpha. Both aminoguanidine and L-NAME blocked the induction of IL-8 mRNA by LPS. Authentic ONOO- (2.5-80 microM) augmented IL-8 mRNA expression and stimulated IL-8 release in a concentration-dependent manner, whereas the NO-releasing compounds, S-nitroso-N-acetyl-DL-penicillamine and sodium nitroprusside failed to induce cytokine production. Combination of the NO-generating chemicals with a superoxide-generating system (xanthine/xanthine oxidase) markedly increased IL-8 release. Enhanced ONOO- formation was detected in granulocytes, monocytes, lymphocytes, and plasma after challenge with LPS. Furthermore, pyrrolidine dithiocarbamate, an inhibitor of activation of nuclear factor-gammaB, markedly attenuated the induction of IL-8 mRNA expression and IL-8 release by either LPS or ONOO-. Our study identifies ONOO- as a novel signaling mechanism for IL-8 gene expression and suggests that inhibition of ONOO- formation or scavenging ONOO- may represent a novel therapeutic approach to inhibit IL-8 production that could lead to reduction of neutrophil accumulation and activation.
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PMID:Peroxynitrite mediates IL-8 gene expression and production in lipopolysaccharide-stimulated human whole blood. 982 May 46

The eosinophilic (EOS) leukocyte has been implicated as a primary effector cell in inflammatory and allergic diseases. Cytokines are among the mediators of inflammatory and allergic diseases which modulate the effector functions of EOS. Certain cytokines, elevated in patients with various allergies, are thought to modulate EOS reactive oxygen species superoxide anion and nitric oxide (NO) responses. Though EOS transcribe and translate mRNA for inducible NO synthase, the effects of cytokines on NO generation remain largely unknown. Thus, we have investigated effects of IL-3, IL-5, GM-CSF, IL-8, RANTES and the proinflammatory cytokines TNF-alpha and IFN-gamma, on superoxide anion and NO generation by clone 15 HL-60 human eosinophilic cells. Cytokine treatments (3 and 18 h) resulted in production of small amounts of superoxide anion which were enhanced by the NO inhibitor L-NAME. In the presence of L-NAME, PMA (1 nM) stimulation significantly increased superoxide anion generation following 3 h treatments with IL-3, TNF-alpha or IFN-gamma. Eighteen hour cytokine treatments with GM-CSF, IL-8, RANTES, IFN-gamma or TNF-alpha primed the cells for enhanced reactive oxygen species following exposure to an EOS stimulant. Inhibition of NO synthesis resulted in increased levels of superoxide anion. Collectively, these results suggest that an environment of proinflammatory cytokines may potentiate the generation of reactive oxygen species by EOS. These results further suggest that at an inflammatory site or during an allergic response, EOS may concomitantly synthesize NO and generate superoxide anion, fractions of which may rapidly react to form the potent oxidant peroxynitrite.
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PMID:Cytokines potentiate human eosinophil superoxide generation in the presence of N(omega)-nitro-L-arginine methyl ester. 1068 1

The incidence of severe invasive disease caused by serogroup A streptococci (GAS) is increasing, and to elucidate the role of streptococcal cell wall components in the inflammatory response, human whole blood was stimulated with lipoteichoic acid (LTA, 0.005-50 microg/mL) and peptidoglycan (10 and 100 microg/ml) from Streptococcus pyogenes. Both stimulants increased dose dependently the leukocyte release of cytokines many thousand fold: tumor necrosis factor alpha (0 to 158,000+/-4,900 pg/mL), interleukin (IL)-1beta (85+/-56 to 31,000+/-4,600 pg/mL), IL-6 (30+/-11 to 34,800+/-15,000 pg/mL), and IL-8 (300+/-150 to 29,000+/-14,000 pg/mL). Intracellular leukocyte levels of reactive oxygen species (ROS) as measured by flow cytometry increased 15-20 fold, from 25 to 400-500 mean fluorescence intensity. Aminoethyl-isothiourea (AE-ITU), a relatively selective inhibitor of the inducible nitric oxide synthase (iNOS) and a ROS scavenger, reduced the cytokine production by 70-100%, and intracellular leukocyte ROS levels by 50-70% (all P < 0.05). The non-selective NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) did not affect intracellular ROS levels, but it caused a moderate selective inhibition of IL-8 production. Leukocyte NO production (measured up to 36 h) was not enhanced by LTA, peptidoglycan, inactivated streptococci, or cytokine combinations. The mechanisms for the anti-inflammatory effects of AE-ITU may be through a reduction of intracellular ROS levels, or through a direct effect on signal transduction, whereas NO modulation is an unlikely mechanism.
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PMID:Aminoethyl-isothiourea inhibits leukocyte production of reactive oxygen species and proinflammatory cytokines induced by streptococcal cell wall components in human whole blood. 1138 18

To investigate the effect of neutrophil adherence to epithelial cells on the release of interleukin 8 (IL-8), we measured neutrophil adherence in the presence or absence of IFN-gamma+TNF-alpha+IL-1beta (cytomix) stimulation on cultured A549 epithelial cells. The extent of neutrophil adherence to A549 epithelial cells was measured and the concomitant production of IL-8 and nitrite were assayed. The roles of adhesion molecules and nitrite in modulation of neutrophil adherence were examined by pretreatment with oversaturating ICAM-1 blocking antibody and L-NAME (1 mM), respectively. There was a time-dependent spontaneous and cytomix-induced release of IL-8 from epithelial cells, as well as a time-dependent increase in the magnitude of neutrophil adherence to epithelial cells. Stimulation of epithelial cells with cytomix induced a further increase in neutrophil adherence. Pretreatment with oversaturated ICAM-1 monoclonal antibody inhibited neutrophil adherence with or without cytomix stimulation. The inhibition of neutrophil adherence to epithelial cells with ICAM-1 monoclonal antibody or a semipermeable membrane downregulated the release of IL-8 with or without cytomix stimulation. Stimulation with cytomix decreased nitrite production. Both neutrophil adherence and L-NAME pretreatment significantly inhibited the production of nitrite. The inhibition of neutrophil adherence to epithelial cells with ICAM-1 monoclonal antibody or a semipermeable membrane upregulated nitrite production. Pretreatment with L-NAME failed to modify the spontaneous release of IL-8, but significantly enhanced the response to adherence and cytomix. In conclusion, endogenous nitric oxide may play a role in preventing neutrophil adherence to lung epithelial cells, thus modulating concomitant IL-8 release.
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PMID:Endogenous nitric oxide inhibits neutrophil adherence to lung epithelial cells to modulate interleukin-8 release. 1152 57

Oxidized-1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (Ox-PAPC), found in atherosclerotic lesions and other sites of chronic inflammation, activates endothelial cells (EC) to synthesize chemotactic factors, such as interleukin (IL)-8. Previously, we demonstrated that the sustained induction of IL-8 transcription by Ox-PAPC was mediated through the activation of sterol regulatory element-binding protein (SREBP). We now present evidence for the role of endothelial nitric oxide synthase (eNOS) in the activation of SREBP by Ox-PAPC. Ox-PAPC treatment of EC induced a dose- and time-dependent activation of eNOS, as measured by phosphorylation of serine 1177, dephosphorylation of threonine 495, and the conversion of L-arginine to L-citrulline. Activation of eNOS by Ox-PAPC was regulated through a phosphatidylinositol-3-kinase/Akt-mediated mechanism. These studies also demonstrated that pretreatment of EC with NOS inhibitor, Nomega-nitro-L-arginine-methyl ester (L-NAME), significantly inhibited Ox-PAPC-induced IL-8 synthesis. Because SREBP activation had been previously shown to regulate IL-8 transcription by Ox-PAPC, we examined the effects of L-NAME on Ox-PAPC-induced SREBP activation. Our data demonstrated that Ox-PAPC-induced SREBP activation and expression of SREBP target genes were significantly reduced by pretreatment with L-NAME. Interestingly, treatment of EC with NO donor, S-nitroso-N-acetylpenicillamine, did not activate SREBP, suggesting that NO alone was not sufficient for SREBP activation. Rather, our findings indicated that superoxide (O2*-), in combination with NO, regulated SREBP activation by Ox-PAPC. We found that Ox-PAPC treatment generated O2*- through an eNOS-mediated mechanism and that mercaptoethylguanidine, a peroxynitrite scavenger, reduced SREBP activation by Ox-PAPC. Taken together, these findings propose a novel role for eNOS in the activation of SREBP and SREBP-mediated inflammatory processes.
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PMID:Role of endothelial nitric oxide synthase in the regulation of SREBP activation by oxidized phospholipids. 1657 11


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