Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The production of superoxide anion (O2-) by phagocytic cells plays an important role in host defenses and inflammatory processes. Interferon-gamma (IFN-gamma) primes neutrophils for increased O2- release stimulated by various agonists. This study examines if myeloid differentiated HL-60 cells also serve as a model for IFN-gamma-induced priming, and examines mechanism by which this priming occurs. IFN-gamma enhanced HL-60 cell superoxide production in response to F-Met-Leu-Phe (FMLP) in a concentration-dependent manner. Following a 4-h exposure, an increase in O2- production was seen with IFN-gamma at 0.1 U/ml, with optimal priming at 100 U/ml. The time course of priming by 100 U/ml IFN-gamma showed that at least a 1-h exposure was required, and a maximal effect was seen at 24 h. Priming after a 4-h exposure to 100 U/ml IFN-gamma was completely inhibited by 1 micrograms/ml cycloheximide. HL-60 cells cultivated with 100 U/ml IFN-gamma produced increased O2- when exposed to 25 mM NaF (containing AIF4) or 10 nM phorbol myristate acetate, agonists that trigger the respiratory burst independent of receptor stimulation. These results indicate that IFN-gamma primes the HL-60 cell respiratory burst in a concentration and time-dependent manner similar to its effect on neutrophils. The data are consistent with the hypothesis that IFN-gamma primes HL-60 cells, in part, by stimulating synthesis of proteins that participate in NADPH oxidase activation distal to the FMLP receptor.
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PMID:Interferon-gamma enhances superoxide production by HL-60 cells stimulated with multiple agonists. 165 64

Research over the past year has revealed several interesting advances in the biosynthesis of the superoxide anion and nitric oxide. Highlights include the demonstration that the G protein Rac 2 is required for NADPH oxidase activation, the finding that nitric oxide is a feedback inhibitor of nitric oxide synthase isoforms, and the discovery that the continuous catalytic activity of the immune/inflammatory nitric oxide synthase is due to strong calmodulin binding, which is independent of elevated calcium levels. Interferon-gamma primes neutrophils and macrophages for both O2- and nitric oxide synthesis. However, NADPH oxidase and immune/inflammatory nitric oxide synthase are differentially regulated such that their activities are not simultaneously induced.
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PMID:Assembly and regulation of NADPH oxidase and nitric oxide synthase. 751 23

Different Stat proteins are activated through phosphorylation of unique tyrosine residues in response to different cytokines and growth factors. Interferon-gamma activates Stat1 molecules that form homodimers and bind cognate DNA elements. Here we show that treatment of permeabilized cells with 200-500 microM peroxo-derivatives of vanadium, molybdenum, and tungsten results in the accumulation of constitutively phosphorylated Stat1 alpha molecules. In contrast, treatment of permeabilized cells with orthovanadate, vanadyl sulfate, molybdate, and tungstate at the same range of concentrations does not result in the accumulation of activated Stat1 alpha molecules in the absence of ligand. However, these compounds inhibit the inactivation of interferon-gamma-induced DNA-binding activity of Stat1 alpha. A 4-6-h exposure of the permeabilized cells to orthovanadate, molybdate, and tungstate, but not vanadyl sulfate, results in a ligand-independent activation of Stat1 alpha, which is blocked by the inhibition or depletion of NADPH oxidase activity in the cells, indicating that NADPH oxidase-catalyzed superoxide formation is required for the bioconversion of these metal oxides to the corresponding peroxo-compounds. Interestingly, ligand-independent Stat1 alpha activation by peroxo-derivatives of these transition metals does not require Jak1, Jak2, or Tyk2 kinase activity, suggesting that other kinases can phosphorylate Stat1 alpha on tyrosine 701.
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PMID:Roles of protein-tyrosine phosphatases in Stat1 alpha-mediated cell signaling. 759 50

Chronic granulomatous disease is a rare, genetically heterogeneous group of disorders in which NADPH oxidase deficiency severely hampers the ability of phagocytes to kill ingested microorganisms. Characterized by recurrent pyogenic infections with granuloma and abscess formation, the disease appears in childhood and may be fatal. Conventional therapy consists of prophylactic trimethoprim-sulfamethoxazole and aggressive infection control measures. Interferon-gamma (IFN-gamma) has been shown in vitro and in vivo to correct alterations of oxidative metabolism. In the most recent multicenter study, IFN-gamma was efficacious in reducing the frequency of severe infections; however, at odds with previous results, this effect appeared to be due to some mechanism other than improvement in respiratory burst function. Although further studies are needed to elucidate the mechanisms of IFN-gamma's action, it appears to have potential application in many infectious diseases.
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PMID:Conventional versus interferon-gamma therapy in chronic granulomatous disease. 843 18

The aim of this work was to analyze the effect of Interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) on NADPH oxidase activity and gp91-phox gene expression in human colostrum macrophages (CM), peripheral blood monocytes (PBM), and myelomonocytic THP-1 cells. We also investigated the effect of IFN-gamma on the release of TNF-alpha by these cells. Our results show that under basal culture conditions, CM release more superoxide than PBM and THP-1 cells (p < 0.05). The addition of IFN-gamma, alone or in combination with TNF-alpha, increased spontaneous superoxide release by PBM and THP-1 cells (p < 0.05) and increased phorbol myristate acetate (PMA)-stimulated superoxide release by CM, PBM, and THP-1 cells (p < 0.05). The NADPH oxidase activity of THP-1 cells consistently remained lower than that of CM or PBM, despite a dramatic response to IFN-gamma and TNF-alpha. Under basal conditions, gp91-phox gene expression was significantly higher in CM and PBM compared with THP-1 cells (p < 0.05). The addition of IFN-gamma alone or in combination with TNF-alpha caused a dramatic increase in gp91-phox gene expression in THP-1 cells (p < 0.05) but not in CM or PBM. Under basal conditions or in the presence of IFN-gamma, CM released more TNF-alpha than PBM or THP-1 cells (p < 0.05). In addition, PBM released more TNF-gamma than THP-1 cells (p < 0.05). IFN-gamma did not significantly augment the release of TNF-alpha by these cells (p > 0.05). Thus, IFN-gamma and TNF-alpha induced equivalent gp91-phox gene expression in THP-1 cells compared with CM or PBM but did not bring about equivalent NADPH oxidase activity. TNF-alpha release was higher in more mature cells. This partial divergence of gp91- phox gene expression, NADPH oxidase activity, and TNF-alpha release is probably a consequence of different events of myeloid cell biology and relates at least in part to cell differentiation state.
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PMID:The effect of IFN-gamma and TNF-alpha on the NADPH oxidase system of human colostrum macrophages, blood monocytes, and THP-1 cells. 1618 Oct 54

Interferon-gamma (IFN-gamma)/lipopolysaccharide (LPS) induces delayed dopaminergic neuron loss in midbrain slice cultures, because of nitric oxide production resulting from p38 mitogen-activated protein kinase (p38 MAPK)-dependent induction of inducible nitric oxide synthase (iNOS). In this study, we show that inhibition of c-Jun N-terminal kinase (JNK), but not of extracellular signal-regulated kinase, protects dopaminergic neurons from IFN-gamma/LPS-induced degeneration. In contrast to a p38 MAPK inhibitor, SB203580, however, a JNK inhibitor, anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), did not suppress IFN-gamma/LPS-induced iNOS expression and nitric oxide production. Involvement of NADPH oxidase-derived superoxide production in dopaminergic neurodegeneration was not obvious, in that superoxide dismutase/catalase or manganese 3-methoxy-N,N'-bis(salicylidene)ethylenediamine chloride (EUK-134), a superoxide dismutase/catalase mimetic, did not afford neuroprotection. Moreover, the NADPH oxidase inhibitors apocynin and diphenylene iodonium were protective against IFN-gamma/LPS cytotoxicity only at concentrations that suppressed nitric oxide production. Notably, alpha-tocopherol effectively prevented IFN-gamma/LPS-induced dopaminergic neuron degeneration, without affecting iNOS induction and nitric oxide production. These results underscore the neuroprotective potential of JNK inhibitor and alpha-tocopherol, in the sense that both agents could rescue dopaminergic neurons under inflammatory conditions associated with robust increases in nitric oxide production.
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PMID:c-Jun N-terminal kinase inhibition and alpha-tocopherol protect midbrain dopaminergic neurons from interferon-gamma/lipopolysaccharide-induced injury without affecting nitric oxide production. 1630 44

Inflammatory monocytes and macrophages have been identified as key players in the pathogenesis of atherosclerosis, arterial hypertension, and myocardial infarction (MI). They become powerful mediators of vascular inflammation through their capacity to secrete and induce the production of proinflammatory cytokines, chemokines and adhesion molecules and through the production of reactive oxygen species mainly via their NADPH oxidase. Importantly, a crosstalk exists between NK cells and monocytes that works via a feedforwad amplification loop of T-bet/Interferon-gamma/interleukin-12 signaling, that causes mutual activation of both NK cells and monocytes and that fosters recruitment of inflammatory cells to sites of inflammation. Recently, we have discovered that this crosstalk is crucial for the unrestricted development of angiotensin II (ATII) induced vascular injury in arterial hypertension, the most important risk factor for atherosclerosis and cardiovascular disease worldwide. In this review, we will also discuss possible implications of this interplay between NK cells and monocytes for the pathogenesis of coronary atherosclerosis and myocardial infarction and potential therapeutic options.
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PMID:Interplay of NK cells and monocytes in vascular inflammation and myocardial infarction. 2517 97