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)

We examined the mechanisms responsible for the regulation by interferon-gamma (IFN-gamma) of the expression of the genes encoding the high affinity IgG-Fc receptor (Fc gamma R-I, CD64) and the NADPH oxidase 47-kDa cytosolic factor (p47-phox) in human polymorphonuclear leukocytes (PMN). Nuclear run-on transcriptional assays demonstrated that the Fc gamma R-I gene transcription is undetectable in untreated PMN but is significantly induced by IFN-gamma. Unlike Fc gamma R-I, p47-phox gene transcription is constitutively active in resting PMN and is down-regulated by a 2-h treatment of these cells with IFN-gamma. The transcriptional modulation by IFN-gamma of Fc gamma R-I and p47-phox genes is not influenced by the protein synthesis inhibitor cycloheximide. Moreover, Northern blot analysis revealed that cycloheximide superinduces p47-phox mRNA expression by increasing its half-life and without affecting p47-phox gene transcription. These findings indicate that human PMN can regulate gene expression by transcriptional and posttranscriptional events.
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PMID:Interferon-gamma transcriptionally modulates the expression of the genes for the high affinity IgG-Fc receptor and the 47-kDa cytosolic component of NADPH oxidase in human polymorphonuclear leukocytes. 183 66

Studies on the role of microtubule integrity in stimulus-response coupling in neutrophils have generated contradictory data. To determine the role of microtubule integrity in stimulus-response coupling elicited by two different mechanisms, i.e., engagement of the Fc receptors (FcR gamma II, FcR gamma III) or engagement of the receptor for FMLP, we utilized colchicine (10 microM), which reduces pericentriolar microtubules to 29% of control, and compared its effect with that of nocodazole (50 microM) and lumicolchicine (10 microM). We now demonstrate that treatment of neutrophils with colchicine but not lumicolchicine, inhibits degranulation elicited by engagement of Fc receptors but augments degranulation in response to FMLP. In contrast to the ligand-specific effect of microtubule-disruption on degranulation, superoxide anion production (assembly of the NADPH oxidase) is unaffected by colchicine regardless of the ligand. To determine whether intact microtubules were required for responses elicited by ligation of Fc gamma RII(CD32) or Fc gamma RIII(CD16), mAb directed against these receptors were employed. Treatment of neutrophils with mAb KuFc79 directed against Fc gamma RII(CD32) or mAb 3G8 directed against Fc gamma RIII(CD16) inhibited degranulation of neutrophils elicited by immune complexes (IC). In contrast, removal of most of Fc gamma RIII by phosphatidylinositol-specific phospholipase C did not significantly alter degranulation in response to IC. We conclude that degranulation elicited by IC results from ligation of both Fc gamma RII and phosphatidylinositol-specific phospholipase C-insensitive Fc gamma RIII. The importance of microtubule integrity on the generation of intracellular signals was also examined. Degranulation of neutrophils proceeds via pertussis toxin-sensitive and insensitive pathways; treatment of cells with colchicine did not augment the action of pertussis toxin. Stimulation of neutrophils by chemoattractants results in a biphasic increase in 1,2-sn-diacylglycerol; a rapid increase ("triggering") secondary to the action of a phosphatidylinositol-specific phospholipase C, and a late increase ("activation") secondary to the action of a phosphatidylcholine-specific phospholipase C. Treatment of cells with colchicine altered the production of both [3H]-arachidonic acid-diacylglycerol and diacyl[14C]glycerol in parallel to its effect on degranulation. These studies indicate that the requirement of intact microtubules for degranulation is ligand-specific. Furthermore, assembly of the respiratory burst oxidase does not require intact microtubules. Microtubules most likely alter the cycling of specific receptors or the generation of specific intracellular signals required for stimulus-response coupling in the course of degranulation. Intact microtubules are not uniformly required for the discharge of granule contents during exocytosis.
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PMID:Differences in signal transduction between Fc gamma receptors (Fc gamma RII, Fc gamma RIII) and FMLP receptors in neutrophils. Effects of colchicine on pertussis toxin sensitivity and diacylglycerol formation. 184 87

When exposed to hen ovalbumin (OA)-complexed IgG antibodies, guinea-pig macrophages undergo O2- generation and a rapid rise in the intracellular concentration of free Ca2+ ((Ca2+]i). These responses were found to depend on the IgG isotype of antibodies used; OA-complexed IgG2 antibody (OA gamma 2) induced these responses 3-5 times more intensively than did OA-complexed IgG1 antibody (OA gamma 1). The inhibitory effects of monoclonal antibody to Fc gamma receptor for IgG2 alone (Fc gamma 2R) and that to Fc gamma receptor for both IgG1 and IgG2 (Fc gamma 1/gamma 2R) showed that Fc gamma 2R triggered both an increase in [Ca2+]i and activation of the respiratory burst NADPH oxidase more effectively than did Fc gamma 1/gamma 2R. As the number of Fc gamma 2R molecules per macrophage is about one-half that of Fc gamma 1/gamma 2R molecules, the ability of Fc gamma 2R to trigger these responses may be much higher than that of Fc gamma 1/gamma 2R. This difference between their abilities was further demonstrated by measuring the responses induced by cross-linking of Fc gamma 2R or Fc gamma 1/gamma 2R molecules. In addition, the O2- generation with OA gamma 1 was found to be enhanced with cytochalasin B, and to be lowered by depletion of the intracellular Ca2+ of macrophages with Ionomycin and EGTA, though cytochalasin B and the Ca2+ depletion did not affect the O2- generation with OA gamma 2. These results suggest that the mechanisms of Fc gamma 2- and Fc gamma 1/gamma 2 R-mediated signal transmission leading to activation of the NADPH oxidase also differ from each other.
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PMID:Different abilities of two types of Fc gamma receptor on guinea-pig macrophages to trigger the intracellular Ca2+ mobilization and O2- generation. 214 7

The capacity to generate superoxide anion (O2-) can be induced in U937 cells by various agents known to cause myeloid cell differentiation. Other reported differentiation events include diminished cell proliferation and the induction by gamma-interferon (IFN gamma) of Fc receptors for immunoglobulin G1 (Fc gamma RI). In this study, we differentiated U937 cells and high Fc gamma RI-expression mutants of U937 cells by treating them with IFN gamma. We compared the time courses over which surface Fc gamma RI became maximal, NADPH oxidase activity was induced, and the antiproliferative effect of IFN gamma was detected. Oxidase activity was measured by stimulating cells with PMA or by activating surface Fc gamma RI using aggregated human IgG1 or second antibody crosslinking of mAb 32/Fc gamma RI complexes. We found that IFN gamma in the absence of additional lymphokines induced high levels of oxidase activity in maximally differentiated U937 cells with even higher levels in the fully differentiated high-Fc gamma RI expression mutants (greater than 8 nmoles/10(6) cells/min for A12.13 cells). Over the course of differentiation, maximal induced levels of Fc gamma RI were reached after 1 to 2 days of IFN gamma treatment, prior to the antiproliferative effect of the lymphokine. In contrast, oxidase activity was induced after a lag of approximately 2 days, becoming maximal only after 4 to 6 days of IFN gamma treatment. This comparison of the induction of Fc gamma RI with that of oxidase activity triggered through Fc gamma RI indicated that the rapid increase of surface receptor was not accompanied by a completion of the pathway of Fc gamma RI-mediated oxidase activity. However, the time courses of induction detected by PMA and Fc gamma RI-agonists were coincident suggesting that the development of oxidative capacity could be due to the induction of components required by both the PMA- and surface receptor-mediated pathways. There are several oxidase components that are known to be IFN gamma-inducible, such as the oxidase flavoprotein, a b558 cytochrome peptide, and oxidase-requiring cytosolic components, and it is possible that one or a set of these components could be the limiting factor(s) for IFN gamma-induced oxidase activity.
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PMID:Functional comparison of the inductions of NADPH oxidase activity and Fc gamma RI in IFN gamma-treated U937 cells. 216 Jun 4

Cross-linking of the high affinity Fc receptor for human immunoglobulin G1 (Fc gamma RI) on U937 cells triggered superoxide anion (O-2) release. This was accomplished by the binding of an Fc gamma RI-specific monoclonal antibody, mAb 32, followed by cross-linking of the mAb on the cell with anti-mouse IgG F(ab')2 by Fc gamma RI-specific mAbs 32 and 22 used as an equimolar mixture or by Fc gamma RI-specific mAb 197 (a murine IgG2a and thus a multivalent ligand for Fc gamma RI) alone. At subsaturating concentrations of the Fc gamma RI-cross-linking ligands, O2- generation was continuous over relatively long intervals. However, saturating concentrations triggered an often substantial but always transient O2- burst. This transient burst of oxidase activity ceased with maximal ligand accumulation on the cell. Cells in which oxidase activity had ceased could be restimulated using phorbol 12-myristate 13-acetate or aggregated human IgG1, indicating that cessation of O2- generation was not due to a generalized exhaustion or inhibition of the NADPH oxidase pathway. Cells incubated in subsaturating concentrations of cross-linking antibodies continued to release O2- until binding of the ligand ceased. In addition, the rates of O2- production and ligand accumulation were the same. Thus, continuous O2- production appeared to be dependent upon continuous de novo formation of cross-linked and activated Fc gamma RI. Furthermore, the mol of O2- released in response to Fc gamma RI cross-linking by the multivalent ligand mAb 197 were directly proportional to the mol of mAb bound over a range of saturating and subsaturating concentrations. This evidence suggests a quantal relationship between each Fc gamma RI activated (cross-linked) and the resultant oxidase activity and supports a "rate" model for the activation of this response. Thus, each Fc gamma RI entering the pool of activated receptors probably makes a unitary contribution to the signal. An additional finding showed that cross-linked Fc gamma RI became associated with the cell cytoskeleton and that this association was also transient. Dissociation of Fc gamma RI from its cytoskeletal attachment occurred well after cessation of O2- production.
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PMID:Cross-linking of the high affinity Fc receptor for human immunoglobulin G1 triggers transient activation of NADPH oxidase activity. Continuous oxidase activation requires continuous de novo receptor cross-linking. 254 82

It is well known that Fc gamma R mediate the rapid release of agents of inflammation and, in addition, play an important role in the uptake of stimulatory antibody complexes. Activation of the FcR for human IgG1 (Fc gamma RI) on human monocytic cells triggers a transient activation of the NADPH oxidase. In this study, we tested the possibility that transience of the NADPH oxidase activation might have been the result of rapid internalization of cross-linked Fc gamma RI. Stimulatory receptor moieties were formed by cross-linking Fc gamma RI with receptor-specific mAb that are known to trigger superoxide anion release. The formation of the stimulatory receptor units was determined by quantitating the rate of superoxide anion production through its reduction of cytochrome c. This rate has been found to correlate with the rate of binding of cross-linking antibody and, therefore, the rate of formation of the stimulatory moieties (receptor aggregates). Internalization of cross-linked Fc gamma RI was measured by quantitation of cell-associated FITC-labeled Fc gamma RI-specific mAb resistant to acid elution. We found that cross-linking antibody bound to Fc gamma RI continued to be taken up by the cells well after cessation of oxidase activity. The constant rate of uptake and the differential effect of temperature on these two functions suggested that they are separately regulated. Quantitation of cross-linked receptors that were inactive, i.e., no longer stimulating superoxide anion production, indicated that 50% of internalizable, and therefore cross-linked, Fc gamma RI remained on the surface after oxidase activity had ceased. This evidence of cessation of oxidase activity before the endocytic uptake of mAb/R stimulatory units indicates that the activated state of surface cross-linked Fc gamma RI is of brief duration and that occupation of the receptors by cross-linking-ligand does not sustain the activated state of the receptor. Thus, Fc gamma RI-mediated oxidase activation is temporally limited to the formation of the stimulatory receptor moiety.
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PMID:Transient activation of the NADPH oxidase through Fc gamma RI. Oxidase deactivation precedes internalization of cross-linked receptors. 255 66

When guinea-pig polymorphonuclear leukocytes (PMNs) are stimulated with hen ovalbumin (OA)-complexed IgG antibodies, they generate superoxide anion (O2-). This reaction was found to depend on the IgG isotype used for preparation of the immune complexes; OA-complexed IgG2 antibody (OA-IgG2) induced 3-4 times more intensively O2- generation than OA-complexed IgG1 antibody (OA-IgG1). The O2- generation with OA-IgG1 was almost completely inhibited by a monoclonal antibody to the Fc gamma R binding both IgG1 and IgG2 (Fc gamma 1/gamma 2 R), whereas that with OA-IgG2 was only slightly inhibited. Since guinea-pig PMNs are capable of binding OA-IgG2 not only through Fc gamma 1/gamma 2 R but also through another Fc gamma R which is specific for IgG2 alone (Fc gamma 2 R), the O2- generation with OA-IgG2 may be mainly mediated by Fc gamma 2 R. In addition, cytochalasin B was found to enhance markedly the O2- generation with OA-IgG1, though that with OA-IgG2 was only slightly affected. The results so far obtained indicate that Fc gamma 1/gamma 2 R and Fc gamma 2 R differ from each other in their activities for triggering O2- generation, namely activation of the respiratory burst NADPH oxidase. Furthermore, differing from the activation of the NADPH oxidase mediated by Fc gamma 2 R, that by Fc gamma 1/gamma 2 R was shown to be suppressed by some cytochalasin B-inhibitable factor or process though its biochemical nature is unknown.
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PMID:Two distinct Fc gamma Rs on guinea-pig polymorphonuclear leukocytes differ from each other in their eliciting activities for O2- generation. 296 27

Cooperation among plasma membrane receptors in activating signal transduction cascades is not well understood. For almost 20 years, it has been clear that when a particulate foreign body is opsonized with complement as well as IgG, the efficiency of IgG effector functions is markedly enhanced. However, the molecular mechanisms involved in cooperation between IgG Fc receptors and complement receptors have not been elucidated. In this work, we show that when human neutrophils (PMN) are plated on a surface coated with both anti-CR3 and anti-Fc gamma RIII antibodies, the respiratory burst which occurs is equivalent to that stimulated by anti-Fc gamma RII. The CR3 ligand iC3b is as effective as anti-CR3 for cooperating with anti-Fc gamma RIII in generation of a respiratory burst. The synergy between CR3 and Fc gamma RIII for activating the NADPH oxidase is abolished by Fab of anti-Fc gamma RII. Nonetheless, the observed synergy is not an artifact of unintended Fc gamma RII ligation, since (a) only this combination of antibodies works to generate H2O2; (b) coating plates with either of the antibodies alone cannot activate the respiratory burst at any dose; (c) LAD (CR3 deficient) cells, which are perfectly competent to mount a respiratory burst when Fc gamma RII is engaged, are incapable of activating the respiratory burst when adherent to wells coated with anti-Fc gamma RIII and anti-CR3; (d) direct engagement of Fc gamma RII activates the respiratory burst by a pathway pharmacologically distinguishable from the synergistic respiratory burst. Fc gamma RIII/CR3 synergy is abolished by cytochalasin B and herbimicin, suggesting that both the actin cytoskeleton and tyrosine phosphorylation are necessary for activation of the synergistic respiratory burst. Further analysis shows that CR3 and Fc gamma RIII have distinct roles in activation of this Fc gamma RII-dependent assembly of the NADPH oxidase. Ligation of CR3 is sufficient to lead to Fc gamma RII association with the actin cytoskeleton on the adherent PMN surface. Coligation of Fc gamma RIII is required for tyrosine phosphorylation of Fc gamma RII. These data are consistent with a model in which phosphorylation of Fc gamma RII or a closely associated substrate initiates activation of a signal transduction pathway leading to oxidase assembly. These are the first data to demonstrate a molecular mechanism for synergy between IgG Fc and complement receptors in activation of phagocyte effector functions.
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PMID:CR3 (Mac-1, alpha M beta 2, CD11b/CD18) and Fc gamma RIII cooperate in generation of a neutrophil respiratory burst: requirement for Fc gamma RIII and tyrosine phosphorylation. 751 90

Human type 1 Fc gamma receptors (Fc gamma RI) bind with high affinity (Kd = approximately 10(-9) M) Fc regions of monomeric IgG1 and IgG3. As demonstrated in this report, interaction of IgG-Fc with the ligand binding site on Fc gamma RI alters its capacity for aggregation-dependent signaling. This Fc-dependence was demonstrated in normal monocytes and U937-10.6 cells exposed to monomeric IgG and then to anti-Fc gamma RI F(ab')2 that cross-link the receptor. Using O2- production to measure cell signaling, we found that binding by high affinity IgGs of various species, as well as by murine hybrid IgGs containing only one high affinity heavy chain, resulted in a marked increase in Fc gamma RI-mediated signaling. Preaggregated Fc gamma RI/IgG had a ratio of one. IgG binding after aggregation of unligated Fc gamma RI did not restore signaling. Dose responses indicated that concentrations of IgG that saturated Fc gamma RI optimized transductional activity. The inclusion of unligated with ligated Fc gamma RI in aggregates depressed activity, indicating a lack of trans-activation of unligated Fc gamma RI. Significantly, IgG-binding markedly increased aggregation-dependent tyrosine phosphorylation of Fc gamma RI gamma-chains and the association of tyrosine phosphorylated Syk. Thus, the consequences of IgG-Fc binding were increases in aggregation-dependent phosphorylation of Fc gamma RI gamma-chains, recruitment of pp72Syk to Fc gamma RI, and signaling of the NADPH oxidase pathway.
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PMID:A novel role for IgG-Fc. Transductional potentiation for human high affinity Fc gamma receptor (Fc gamma RI) signaling. 771 21

Endotoxemia, in man, has been associated with an autooxidative reduction in the bioavailability of polymorphonuclear leukocyte receptors. The location and mechanisms of this phenomena have remained unclear; we investigated the effects of lipopolysaccharide (LPS) on intracellular Fc gamma receptor expression. Polymorphonuclear leukocytes (PMN) were incubated with LPS (10 ng/ml), permeabilized with saponin, followed by measurement of CD64, CD32w, and CD16 (Fc gamma RI, II, III) using 125I-monoclonal antibodies directed against these receptors. Exposure of permeabilized PMN to LPS significantly reduced intracellular Fc gamma receptor expression. PMN isolated from patients with chronic granulomatous disease or myeloperoxidase-specific deficiency did not exhibit this effect. Furthermore, specific inhibitors of components of the PMN oxidative burst (NaN3, 10 mM; L-alanine 30 mM) prevented the LPS-induced oxidative reduction in receptor expression. NADPH oxidase inhibition with diphenyleneiodonium also blocked the effect of LPS on intracellular Fc gamma receptor expression. The effects of LPS on intracellular PMN Fc gamma receptors were reproduced with monophosphoryl lipid A but required a 10 times greater concentration than LPS. Preadherence of PMN on fibronectin or arginine-glycine-aspartate-serine (RGDS), but not laminin, prevented the LPS-induced reduction in oxidative receptor expression. The effects of fibronectin/RGDS were blocked by actinomycin D and cycloheximide. Cross-linkage of intracellular Fc gamma receptors prior to exposure to LPS also prevented the LPS-induced oxidative reduction in receptor expression. These results demonstrate that an important pathophysiologic property of LPS is to induce an intracellular oxidative-derived reduction in Fc gamma receptor expression and that the biologically relevant proteins fibronectin and RGDS ameliorate this effect.
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PMID:Regulation of intracellular polymorphonuclear leukocyte Fc receptors by lipopolysaccharide. 806 31


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