Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Neutrophils (PMNs) initiate production of toxic oxygen metabolites through stimulation of an NADPH oxidase resulting in the reduction of oxygen to superoxide anion (O2-). The activity of this enzyme system may be primed by a variety of compounds. This laboratory investigated the possibility that stored blood components may contain agents which prime the PMN oxidase. At the time of outdate, packed red blood cells, whole blood, and platelet concentrates contained a priming agent which enhanced the PMN NADPH oxidase activity in response to a soluble stimulus, formyl-Met-Leu-Phe, by 2.1- to 2.8-fold. The priming activity was almost completely inhibited by WEB 2170, a specific platelet activating factor antagonist. Fresh plasma or fresh-frozen plasma did not exhibit priming activity. These data suggest that platelet-activating factor-like compounds are generated during the storage of cellular blood components. The presence of these agents in stored blood may suggest a role for specific compounds which prime PMNs and possibly mediate other effects which result in severe complications of transfusion therapy.
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PMID:Stored blood components contain agents that prime the neutrophil NADPH oxidase through the platelet-activating-factor receptor. 133 55

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

Tumor necrosis factor alpha (TNF) primes human neutrophils (PMN) for enhanced superoxide (O2-) production if cells are subsequently stimulated with the chemotactic peptide, n-formyl-Met-Leu-Phe (fMLP). fMLP activates phospholipase D to form phosphatidic acid (PA), and a correlation may exist between PA production and O2- generation in PMN. Therefore, we assessed the ability of TNF to prime phospholipase D activation in PMN stimulated with fMLP. TNF (100 units/ml) pretreatment primed enhanced PA production in PMN challenged with 1 microM fMLP, in the absence of cytochalasin B, as demonstrated by increased production of tritiated PA from PMN label with 1-O-[9',10'-3H]hexadecyl-2-lyso-sn-glycero-3-phosphocholine ([3H]LPAF) and by increased PA mass. PA was formed via activation of phospholipase D and occurred with minimal production of diglycerides. Production of O2- was also enhanced in identically treated cells, and we demonstrated a direct correlation between enhanced PA formation and O2- production. Conversely, ethanol inhibition of PA formation led to a comparable reduction in O2- generation. This report of priming of phospholipase D by physiological agonists is the only natural system where enhanced PA formation has been dissociated from diglyceride formation. Our results suggest a link between PA production and NADPH oxidase activation in human PMN.
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PMID:Tumor necrosis factor alpha priming of phospholipase D in human neutrophils. Correlation between phosphatidic acid production and superoxide generation. 184 15

The Ca++ ionophore A23187 and phorbol 12-myristate 13-acetate (PMA) caused dose-dependent inhibition of phospholipid (PL) methylation in unfractionated mononuclear cells (MNC), monocytes, and lymphocytes as measured by incorporation of 3H-methyl-groups from [3H-methyl]-L-methionine into phosphatidylcholine (PC), dimethyl phosphatidylethanolamine (PE), and monomethyl PE. This inhibitory effect did not correlate with monocyte superoxide release and was unaltered by the presence of either catalase and superoxide dismutase or the NADPH oxidase inhibitor, diphenylene iodonium (DPI), indicating that oxyradical-mediated oxidation of methionine was not the major cause of inhibition of PL methylation. Furthermore L-adrenaline, which elevates cAMP and does not stimulate superoxide release, also inhibited PL methylation. Inhibition by PMA was not due to reduction in intracellular levels of methionine or S-adenosyl methionine. A23187 caused reduction of S-adenosyl methionine levels only at 1 microM, and had no effect at lower concentrations. Inhibition of PL methylation was shown not to be due to phospholipase A2-dependent hydrolysis of newly methylated PL. Attempts to reverse the inhibitory effect of either A23187 or PMA with the putative protein kinase inhibitors W-7 and H-7 were inconclusive. The mechanism of inhibition of PL methylation by A23187 and PMA remains unclear, but does not appear to be due to oxidation of methionine or hydrolysis of newly methylated PL.
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PMID:Phorbol 12-myristate 13-acetate, A23187 and L-adrenaline inhibit phospholipid methylation in human monocytes and lymphocytes. Inhibition is independent of oxyradical production and phospholipid hydrolysis. 217 46

In neutrophils of patients with essential hypertension the NADPH-dependent O2- production elicited by stimulation with f-Met-Leu-Phe is three to four fold higher in comparison with neutrophils of normotensive control subjects. Neutrophils from hypertensive patients are less responsive to priming, by non-stimulating doses of the agonist, as compared to control cells, which following this pretreatment augment superoxide anion production up to levels close to those expressed by neutrophils from hypertensive patients. No difference in NADPH oxidase activity, between neutrophils from the two groups of subjects, was observed when the rate of O2- production was evaluated in a reconstructed cell-free system containing the membrane fraction and the cytosolic cofactors. These results are consistent with the hypothesis that differences in the functional organization of the oxidase at the membrane level in neutrophils of hypertensive are responsible for the enhanced O2- production following agonist stimulation.
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PMID:Enhanced activation of the respiratory burst oxidase in neutrophils from hypertensive patients. 253 41

In the human premonocytic line U937, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) induces a functional NADPH oxidase, that is responsive to both phorbol esters and opsonized zymosan. The chemotactic peptide f-Met-Leu-Phe (fMLP) did not, however, induce superoxide generation by these cells. This was not due to the absence of receptors for fMLP. Although there was no significant binding of [3H]-fMLP to undifferentiated U937 cells, preincubation with 1,25-(OH)2D3 induced expression of specific and saturable binding sites. Moreover, fMLP induced a rapid and reversible rise in cytosolic free Ca2+ concentration ([Ca2+]i) in 1,25-(OH)2D3-treated U937 cells, but not in control or 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3)-treated cells. This [Ca2+]i response was dependent on concentrations of both fMLP and 1,25-(OH)2D3 and was observed at physiologic concentrations of the hormone (approximately 25 pM). The rise in [Ca2+]i induced by fMLP in 1,25-(OH)2D3-treated U937 cells was blocked by pertussis toxin and presumably mediated by inositol (1,4,5)-trisphosphate generation. These results indicate that in U937 cells differentiated with 1,25-(OH)2D3, inositol phosphate-mediated [Ca2+]i responses to fMLP are uncoupled from NADPH oxidase activation.
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PMID:1,25-dihydroxyvitamin D3 induces responsiveness to the chemotactic peptide f-Met-Leu-Phe in the human monocytic line U937: dissociation between calcium and oxidative metabolic responses. 254 Feb 55

In comparative studies of f-met-Leu-Phe (FMLP) and methionine enkephalin (ME) induced polymorphonuclear leukocyte (PMNL) stimulation the following results were obtained: (i) both FMLP and ME increased the intracellular killing (IK) capability of human PMNLs probably through NADPH oxidase activation, (ii) the ME-induced respiratory burst (RB) differed from the chemotactic peptide FMLP-triggered superoxide generation because the former was not accompanied by the activation of the glutathione system and the duration of the superoxide production was prolonged. The reaction was dependent on lipoxygenation, was potentiated by indomethacin (IM) and was inhibited by nordihidro-guairetic acid (NDGA), (iii) both 14C-arachidonic acid (14C-AA) release and leukotriene B4 (LTB4) synthesis of ME-treated PMNLs were elevated as compared to those of FMLP triggered cells. Our results suggest that lipoxygenation and even an increased LTB4 synthesis are involved in the ME-induced RB of leukocytes.
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PMID:Activation of the lipoxygenase pathway in the methionine enkephalin induced respiratory burst in human polymorphonuclear leukocytes. 283 81

The cell-free system for activation of the neutrophil NADPH oxidase allowed us to examine activation of the oxidase in the absence of its NADPH-dependent turnover. The covalent sulfhydryl-modifying reagent N-ethylmaleimide completely inhibited the activation step (Ki = 40 mumol/L) in the cell-free system but had no effect on turnover of the preactivated particulate NADPH oxidase (up to 1 mmol/L). When N-ethylmaleimide was added to intact neutrophils during the period of maximal O2 generation in response to stimuli that activate the respiratory burst (phorbol myristate acetate, f-Met-Leu-Phe, opsonized zymosan, arachidonic acid), O2- generation ceased within seconds. Study of components of the cell-free activation system indicated that the cytosolic cofactor was irreversibly inhibited by N-ethylmaleimide whereas the N-ethylmaleimide-treated, membrane-associated oxidase could be activated by arachidonate and control cytosolic cofactor. Likewise, the cell-free system prepared from intact neutrophils that had been briefly exposed to N-ethylmaleimide and then washed reflected the effects of N-ethylmaleimide on the isolated cell-free components: cytosolic cofactor activity was absent, but the membrane oxidase remained fully activatable. Thus inhibition of oxidase activation by N-ethylamaleimide unmasked a rapid deactivation step that was operative in intact neutrophils but not in isolated particulate NADPH oxidase preparations. The demonstrated specificity of N-ethylmaleimide for oxidase activation and lack of effect on turnover of the NADPH oxidase suggested that sustained O2- generation by intact neutrophils was a result of continued replenishment of a small pool of active oxidase. The existence of an inactive pool of NADPH oxidase molecules in particulate preparations from stimulated neutrophils was supported more directly by activating these preparations again in the cell-free system.
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PMID:Rapid deactivation of NADPH oxidase in neutrophils: continuous replacement by newly activated enzyme sustains the respiratory burst. 283 55

The effect of various soluble stimuli on the superoxide production by guinea pig eosinophils was studied in comparison to neutrophils. Phorbol myristate acetate, A23187, digitonin, NaF, concanavalin A (Con A), and cytochalasin E stimulated eosinophils and neutrophils to release O2-. The O2- production by these active agents, excluding Con A and cytochalasin E, was much greater in eosinophils than in neutrophils. Formyl-Met-Leu-Phe stimulated the O2- production in neutrophils but not in eosinophils. Neither histamine nor Val/Ala-Gly-Ser-Glu stimulated the O2- production in both types of leukocytes. A23187- or Con A-stimulated O2- production was greatly enhanced by cytochalasin B pretreatment in neutrophils but not in eosinophils. Lineweaver-Burk analysis of NADPH oxidase in particulate fractions showed that eosinophils possessed the same Km values as neutrophils and greater Vmax values than neutrophils, suggesting that eosinophils have a similar, but more active, O2- -generating enzyme system than neutrophils.
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PMID:Response of superoxide anion production by guinea pig eosinophils to various soluble stimuli: comparison to neutrophils. 299 68

The inhibitory effects of gold compounds on the NADPH oxidase system of human polymorphonuclear leukocytes (PMNs) has been investigated. Auranofin (0.5-4.0 micrograms Au/ml) suppressed the rate of superoxide anion generation as well as the total yield in cells stimulated with phorbol myristate acetate and f-Met-Leu-Phe. This implies that drug action may be occurring at the level of protein kinase C or steps subsequent to this in the signal transduction sequence. Sodium aurothiomalate (1-100 micrograms Au/ml) lacked such activity. Neither gold compound altered the ability of the granule-rich fraction of PMNs to produce oxy radicals whether this fraction was obtained from drug-treated cells or was treated after its isolation. Therefore, in order for auranofin to exhibit its inhibitory effects on the NADPH oxidase system, an intact cell membrane is necessary.
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PMID:Effect of gold compounds on NADPH oxidase system of human neutrophils. 301 58


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