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)

To determine the temporal roles of phosphatidylinositol 3-kinase (PI3-kinase) and phospholipase D (PLD) during human neutrophil activation stimulated by a chemotactic peptide, we examined the kinetics of these enzymes and related them to a neutrophil function (superoxide production). Both wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), potent and specific inhibitors of PI3-kinase, inhibit PI3-kinase activity in human neutrophils and significantly inhibit superoxide production from the early phase. Ethanol has no effect on PI3-kinase and markedly inhibits superoxide production at the late phase. Although these agents are inhibitory to different degrees, when neutrophils are simultaneously treated with ethanol and PI3-kinase inhibitors, superoxide is not produced. These results suggest that PI3-kinase and PLD play a pivotal role in the signal transduction pathway of the chemo-attractant-receptor involved neutrophil activation. These enzymes produce second messengers which are required for subsequent superoxide production in human neutrophils. NADPH oxidase is activated in a PI3-kinase-dependent manner at the early phase, and PLD activity follows it and is related to superoxide production at the late phase in human neutrophils by stimulation with FMLP.
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PMID:Roles of phosphatidylinositol 3-kinase and phospholipase D in temporal activation of superoxide production in FMLP-stimulated human neutrophils. 1122 70

Immunoglobulin G (IgG) receptors (FcgammaRs) on myeloid cells are responsible for the internalization of immune complexes. Activation of the oxidase burst is an important component of the integrated cellular response mediated by Fc receptors. Previous work has demonstrated that, in interferon-gamma-primed U937 cells, the high-affinity receptor for IgG, FcgammaRI, is coupled to a novel intracellular signaling pathway that involves the sequential activation of phospholipase D (PLD), sphingosine kinase, and calcium transients. Here, it is shown that both known PLD isozymes, PLD1 and PLD2, were present in these cells. With the use of antisense oligonucleotides to specifically reduce the expression of either isozyme, PLD1, but not PLD2, was found to be coupled to FcgammaRI activation and be required to mediate receptor activation of sphingosine kinase and calcium transients. In addition, coupling of FcgammaRI to activation of the nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) oxidase burst was inhibited by pretreating cells with 0.3% butan-1-ol, indicating an absolute requirement for PLD. Furthermore, use of antisense oligonucleotides to reduce expression of PLD1 or PLD2 demonstrated that PLD1 is required to couple FcgammaRI to the activation of NADPH oxidase and trafficking of internalized immune complexes for degradation. These studies demonstrate the critical role of PLD1 in the intracellular signaling cascades initiated by FcgammaRI and its functional role in coordinating the response to antigen-antibody complexes.
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PMID:Functional coupling of FcgammaRI to nicotinamide adenine dinucleotide phosphate (reduced form) oxidative burst and immune complex trafficking requires the activation of phospholipase D1. 1171 83

Angiotensin II--mediated oxidative stress may play a role in the pathogenesis of coronary atherosclerosis. We examined the effects of pressure on the angiotensin II--mediated increase in oxidative stress and migration of cultured human coronary smooth muscle cells (SMCs). Increased pressure (100 mm Hg) by helium gas for 48 hours increased angiotensin II--mediated oxidative stress as evaluated by flow cytometry and SMC migration (from 15.9 +/- 2.2 to 32.0 +/- 2.4 cells per 4 high-power fields, P<0.05; n=8). The pressure-induced increases in oxidative stress observed appear to involve phospholipase D (PLD) and protein kinase C (PKC), inasmuch as the indirect PLD inhibitor suramin, at 100 micromol/L, and the PKC inhibitor chelerythrine, at 1 micromol/L, completely blocked the increase in angiotensin II--mediated oxidative stress induced by pressure. Pressure-induced increase in angiotensin II--mediated oxidative stress was inhibited by diphenylene iodonium chloride, an NADPH oxidase inhibitor, by 79% (P<0.05, n=8). Losartan (1 micromol/L), its active metabolite E3174 (1 micromol/L), and the antioxidant N-acetylcysteine (100 mmol/L) but not PD123319 (1 micromol/L) also blocked pressure-induced increases in angiotensin II--mediated oxidative stress and SMC migration (P<0.05, n=8). These findings suggest a novel cellular mechanism whereby pressure regulates the angiotensin II--mediated migration of SMCs, possibly via angiotensin II type 1 receptors, and which involves PLD-mediated, PKC-mediated, and NADPH oxidase--mediated increases in oxidative stress.
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PMID:Pressure promotes angiotensin II--mediated migration of human coronary smooth muscle cells through increase in oxidative stress. 1188 85

We show that blockers of phospholipase D (PLD) reduce fMLP-triggered exocytosis of secretory vesicles effectively. In accordance with this, the PLD product phosphatidic acid (PA) was able to induce mobilization of secretory vesicles. Although PLD seems to play a role in the release of all neutrophil granule types, exogenous PA alone was not sufficient to activate the exocytosis of primary and secondary granules, suggesting that in the case of these granules, additional signaling factors are required to initiate the secretory responses. The ADP-ribosylation factor (ARF)-inhibitor brefeldin A (BFA) inhibited the fMLP-stimulated O2*- production strongly, whereas it did not influence any of the exocytic responses, and no significant effect of BFA was detected on the O2*- generation induced by other stimuli. On the basis of these results, we propose that upon chemoattractant stimulation, PLD activity is involved in induction of degranulation and O2*- production, but a BFA-sensitive ARF is only required to the activation of the NADPH oxidase. This ARF action seems to participate exclusively in the signaling pathway between the fMLP receptor and the oxidase.
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PMID:Contribution of phopholipase D and a brefeldin A-sensitive ARF to chemoattractant-induced superoxide production and secretion of human neutrophils. 1192 57

3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a soluble guanylyl cyclase (sGC) activator, inhibited formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide anion (O(2)*(-)) generation and O(2) consumption in rat neutrophils (IC(50) values of 12.7+/-3.1 and 17.7+/-6.9 microM, respectively). Inhibition of O(2)*(-) generation by YC-1 was partially reversed by the cyclic GMP-lowering agent 6-anilinoquinoline-5,8-quinone (LY83583) and by the Rp isomer of 8-(4-chlorophenylthio)guanosine-3',5'-monophosphorothioate (Rp-8-pCPT-cGMPS), a cyclic GMP-dependent protein kinase inhibitor. In cell-free systems, YC-1 failed to alter O(2)*(-) generation during dihydroxyfumaric acid autoxidation, phorbol 12-myristate 13-acetate (PMA)-activated neutrophil particulate NADPH oxidase preparation, and arachidonic acid-induced NADPH oxidase activation. YC-1 increased cellular cyclic GMP levels through the activation of sGC and the inhibition of cyclic GMP-hydrolyzing phosphodiesterase activity. The plateau phase, but not the initial spike, of fMLP-induced [Ca(2+)](i) changes was inhibited by YC-1 (IC(50) about 15 microM). fMLP- but not PMA-induced phospholipase D activation was inhibited by YC-1 (IC(50) about 28 microM). Membrane-associated ADP-ribosylation factor and Rho A in cell activation was also reduced by YC-1 at a similar concentration range. Neither cytosolic protein kinase C (PKC) activity nor PKC membrane translocation was altered by YC-1. YC-1 did not affect either fMLP-induced phosphatidylinositol 3-kinase activation or p38 mitogen-activated protein kinase phosphorylation, but slightly attenuated the phosphorylation of extracellular signal-regulated kinase. Collectively, these results indicate that the inhibition of the fMLP-induced respiratory burst by YC-1 is mediated by cyclic GMP-dependent and -independent signaling mechanisms.
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PMID:Inhibition of superoxide anion generation by YC-1 in rat neutrophils through cyclic GMP-dependent and -independent mechanisms. 1199 25

Granulocyte colony-stimulating factor (GCSF) primes reduced neutrophil nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in response to formyl peptide but does not increase oxidase activity when used alone. Both oxidase activity and degranulation require phospholipase D (PLD) activation, and exogenous C(2)-ceramide inhibits both functions through inhibition of PLD activity. We extended these observations to investigate neutrophil responses to GCSF. GCSF at a dosage of 30 to 100 ng/mL, a concentration range that primes superoxide release, stimulated a 60% to 100% increase in gelatinase release from tertiary granules but did not stimulate lactoferrin release from secondary granules. A 75% to 100% dose-dependent increase in PLD activity in GCSF-treated neutrophils was also observed. Gelatinase release and PLD activity were inhibited by 10 micromol/L C(2)-ceramide. The increase in gelatinase release in response to priming concentrations of GCSF suggests that tertiary granules contribute a component of the NADPH oxidase to the plasma membrane. Neutrophils treated with 50 ng/mL GCSF were found to contain 20% more cytochrome b(558) in the plasma membrane fraction than unstimulated cells, consistent with degranulation of only tertiary granules. Correspondingly, in the presence of 10 micromol/L C(2)-ceramide, cytochrome b(558) content in the plasma membrane did not increase after neutrophil activation. In contrast, GCSF did not lead to p47phox translocation to the plasma membrane or phosphorylation. Because phosphorylation and translocation of p47phox are required for oxidase activity, these findings account for the inability of GCSF alone to generate the respiratory burst. We conclude that translocation of cytochrome b(558) was responsible for GCSF priming of NADPH oxidase in neutrophils.
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PMID:Granulocyte colony-stimulating factor primes NADPH oxidase in neutrophils through translocation of cytochrome b(558) by gelatinase-granule release. 1208 Mar 23

In this study, the cellular localization of the inhibitory effect of a natural flavonoid cirsimaritin against formyl-methionyl-leucyl-phenylalanine (fMLP)-induced respiratory burst in rat neutrophils was investigated. Cirsimaritin concentration-dependently inhibited the superoxide anion (O(*-)(2))generation and O(2) consumption (IC(50) 11.5+/-2.2 micro M and 17.0+/-3.9 micro M, respectively) of neutrophils. Cirsimaritin did not reduce, but slightly enhanced the O(*-)(2) generation in phorbol 12-myristate 13-acetate (PMA)-activated or arachidonic acid-stimulated NADPH oxidase preparation as well as during the autoxidation of dihydroxyfumaric acid. Cirsimaritin did not elevate cellular cAMP levels, and only partially inhibited the fMLP-induced [Ca(2+)](i) changes in the presence or absence of extracellular Ca(2+). The phosphorylation of protein tyrosine, extracellular signal-regulated protein kinase and Akt caused by fMLP were attenuated by cirsimaritin in a concentration-dependent manner. In contrast, cirsimaritin had no effect on the phosphorylation of p38 mitogen-activated protein kinase. Cirsimaritin produced a concentration-dependent reduction in the formation of phosphatidic acid and phosphatidylethanol, in the presence of ethanol, from fMLP-stimulated neutrophils (IC(50) 15.1+/-6.5 micro M and 15.6+/-3.4 micro M, respectively), but did not affect the phosphatidylethanol formation in response to PMA. Under the similar concentration range, cirsimaritin attenuated the membrane translocation of ARF and Rho A. However, the GTPgammaS-stimulated membrane-associated ARF and Rho in cell lysate were unaffected by cirsimaritin. Collectively, these results indicate that the inhibition of fMLP-induced respiratory burst by cirsimaritin in rat neutrophils is likely mainly through the blockade of phospholipase D signaling pathway.
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PMID:Inhibition of formyl-methionyl-leucyl-phenylalanine-stimulated respiratory burst by cirsimaritin involves inhibition of phospholipase D signaling in rat neutrophils. 1223 43

In order to investigate the underlying mechanism of HCl in oesophagitis, the inflammatory response to HCl was observed in RBL-2H3 mast cells. Rat basophilic leukemia (RBL-2H3) cells were used to measure histamine release, arachidonic acid (AA) release, reactive oxygen species (ROS) and peroxynitrite generation induced by HCl. Exogenous HCl increased the level of histamine release and ROS generation in a dose dependent manner, whereas it decreased the spontaneous release of [3H] AA and the spontaneous production of peroxynitrite. Mepacrine (10 microM), oleyloxyethyl phosphorylcholine (10 microM) and bromoenol lactone (10 microM) did not affect both the level of histamine release and ROS generation induced by HCl. U73122 (1 microM), a specific phospholipase C (PLC) inhibitor did not have any influence on level of histamine release and ROS generation. Propranolol (200 microM), a phospholipase D (PLD) inhibitor, and neomycin (1 mM), a nonspecific PLC and PLD inhibitor, significantly inhibited both histamine release and ROS generation. Diphenyleneiodonium (10 microM), a NADPH oxidase inhibitor, and tiron (5 mM), an intracellular ROS scavenger significantly inhibited the HCl-induced histamine release and ROS generation. These findings suggest that the inflammatory responses to HCl is related to histamine release and ROS generation, and that the ROS generation by HCl may be involved in histamine release via the PLD pathway in RBL-2H3 cells.
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PMID:Histamine release by hydrochloric acid is mediated via reactive oxygen species generation and phospholipase D in RBL-2H3 mast cells. 1243 4

The inhibition of formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide anion (O2(.-)) generation by 2-benzyloxybenzaldehyde (CCY1a) was investigated in rat neutrophils, and the underlying mechanism of this inhibition was assessed. CCY1a concentration-dependently inhibited O2(.-) generation (IC(50)=18.5+/-4.3 microM). In cell-free systems, CCY1a failed to alter O2(.-) generation during dihydroxyfumaric acid autoxidation, in phorbol 12-myristate 13-acetate (PMA)-activated neutrophil particulate NADPH oxidase preparations, or during arachidonic acid-induced NADPH oxidase activation. CCY1a increased cellular cyclic AMP (cAMP) levels in a time- and concentration-dependent manner, and this cAMP-elevating effect was inhibited by the adenylyl cyclase inhibitor 9-(tetrahydro-2'-furyl)adenine (SQ22536), adenosine deaminase (ADA), and the adenosine receptor antagonist 8-(p-sulfophenyl)theophylline. In neutrophils, inhibition of O2(.-) generation by CCY1a was partially reversed by the protein kinase A inhibitor (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-l][1,6]benzodiazocine-10-carboxylic acid, hexyl ester (KT5720). CCY1a did not affect fMLP-induced p38 mitogen-activated protein kinase phosphorylation, but concentration-dependently attenuated the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt (IC(50) about 31.3 and 19.4 microM, respectively). The plateau phase, but not the initial spike, of fMLP-induced [Ca2+](i) changes was inhibited by CCY1a in a concentration-dependent manner. CCY1a inhibition of Ca2+ entry, ERK, and Akt phosphorylation was not prevented by SQ22536 or ADA. fMLP-induced phospholipase D (PLD) activation was inhibited by CCY1a (IC(50)=13.9+/-2.0 microM). ADA and KT5720 did not prevent the inhibition of PLD activation by CCY1a. Collectively, these results indicate that the inhibition by CCY1a of fMLP-induced O2(.-) generation in rat neutrophils can probably be attributed to the increase in cAMP levels, and to the blockade of Ca2+ entry, suppression of Akt, and PLD activation via cAMP-independent mechanisms.
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PMID:Investigation of the cellular mechanism of inhibition of formyl-methionyl-leucyl-phenylalanine-induced superoxide anion generation in rat neutrophils by 2-benzyloxybenzaldehyde. 1266 40

The inhibition of formyl-methionyl-leucyl-phenylalanine (fMLP)-induced respiratory burst by 2',5'-dihydroxy-2-furfurylchalcone (DHFC) was investigated in rat neutrophils, and the underlying mechanism of this inhibition was assessed. DHFC concentration-dependently inhibited superoxide anion (O(2)) generation (IC(50) 4.2+/-1.2 microM), reaching a plateau within 5-10 min preincubation time, and inhibited oxygen consumption (IC(50) 6.9+/-1.9 microM) in rat neutrophils. In cell-free systems, DHFC failed to scavenge the generated during dihydroxyfumaric acid auto-oxidation. DHFC was less effective in the inhibition of both phorbol 12-myristate 13-acetate-activated neutrophil particulate NADPH oxidase activity and arachidonic acid-induced NADPH oxidase activation. In rat neutrophils, DHFC did not exert a cAMP-elevating effect, nor did it affect fMLP-induced [Ca(2+)](i) change to a considerable extent. DHFC slightly reduced fMLP-induced phosphatidylinositol 3-kinase (PI3 K) activation but showed moderate inhibition of Akt phosphorylation. fMLP-induced cellular phospholipase D (PLD) activation was markedly inhibited by DHFC (IC(50) 8.9+/-2.0 microM). In addition, DHFC effectively attenuated the membrane association of protein kinase C (PKC)-alpha, ADP-ribosylation factor (ARF) and Rho A in fMLP-stimulated cells. However, DHFC had no effect on the membrane association of ARF and Rho A caused by guanosine 5'-[gamma-thio]triphosphate (GTPgammaS) in cell lysate. fMLP-stimulated protein tyrosine phosphorylation was weakly attenuated by DHFC. DHFC was more efficient in the inhibition of extracellular signal-regulated kinase (ERK) phosphorylation than p38 mitogen-activated protein kinase (MAPK) phosphorylation. Collectively, these results indicate that the suppression of fMLP-induced respiratory burst by DHFC in rat neutrophils is probably mainly attributable to the inhibition of PLD activation, via the blockade of PKC-alpha, ARF and Rho A membrane association.
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PMID:The blockade of formyl peptide-induced respiratory burst by 2',5'-dihydroxy-2-furfurylchalcone involves phospholipase D signaling in neutrophils. 1292 64


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