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 Fas-induced reactive oxygen species (ROS) generation in cells sensitive to Fas-mediated apoptosis, chemiluminescence, a strong indicator of ROS generation, was monitored after stimulation with agonistic anti-Fas. Fas ligation resulted in a rapid and sustained ROS generation. The generation reached a maximum within 5 min and was still observed at least 40 min after the stimulation. No significant ROS generation was observed under conditions where apoptosis was absent. Furthermore, an NADPH oxidase inhibitor, diphenylene iodonium, prevented Fas-mediated ROS generation, suggesting that Fas induces ROS generation via stimulation of the oxidase system.
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PMID:Rapid and specific reactive oxygen species generation via NADPH oxidase activation during Fas-mediated apoptosis. 955 49

Human neutrophils have a short half-life and are believed to die by apoptosis or programmed cell death both in vivo and in vitro. We found that caspases are activated in a time-dependent manner in neutrophils undergoing spontaneous apoptosis, concomitant with other characteristic features of apoptotic cell death such as morphologic changes, phosphatidylserine (PS) exposure, and DNA fragmentation. The treatment of neutrophils with agonistic anti-Fas monoclonal antibodies (MoAbs) significantly accelerated this process. However, in cells treated with the potent neutrophil activator phorbol 12-myristate 13-acetate (PMA), caspase activity was only evident after pharmacologic inhibition of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Similarily, inhibition of the NADPH oxidase in constitutive and Fas/APO-1-triggered apoptosis resulted in increased rather than suppressed levels of caspase activity, suggesting that reactive oxygen species may prevent caspases from functioning optimally in these cells. Moreover, oxidants generated via the NADPH oxidase were essential for PS exposure during PMA-induced cell death, but not for neutrophils undergoing spontaneous apoptosis. We conclude that caspases are an important component of constitutive and Fas/APO-1-triggered neutrophil apoptosis. However, these redox sensitive enzymes are suppressed in activated neutrophils, and an alternate oxidant-dependent pathway is used to mediate PS exposure and neutrophil clearance under these conditions.
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PMID:Involvement of caspases in neutrophil apoptosis: regulation by reactive oxygen species. 984 48

In several human B- and T-lymphoid cell lines, reactive oxygen species (ROS) were produced in a time- and dose-dependent manner in response to menadione (vitamin K3) and anti-Fas (CD95/APO-1) mAb when ROS formation was determined by a chemiluminescence-based method. The ROS evoked by menadione and anti-Fas could be first observed as rapidly as within 20 seconds after the stimulation, reaching a maximum within 5-10 min, and declining slowly thereafter. Both menadione and anti-Fas also induced increased tyrosine phosphorylation of multiple cellular proteins whose pattern was similar to that observed upon hydrogen peroxide treatment. For each agent, the kinetics of the increased tyrosine phosphorylation was similar to that of ROS production, and an NADPH oxidase inhibitor, diphenyleneiodonium, prevented both of these two events. Our results suggest a close link between ROS production and tyrosine phosphorylation induced by divergent extracellular stimuli and the possible role of NADPH oxidase or its related enzyme.
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PMID:Involvement of reactive oxygen species produced via NADPH oxidase in tyrosine phosphorylation in human B- and T-lineage lymphoid cells. 1004 96

Diphenyleneiodonium (DPI) is a broad-spectrum flavoprotein inhibitor commonly used to inhibit oxidant production by the NADPH oxidase of phagocytic and nonphagocytic cells. A previous study has shown that DPI can sensitize T24 bladder carcinoma cells to Fas-mediated apoptosis. We observed DPI to deplete intracellular reduced glutathione (GSH) in T24 cells and a range of other primary and transformed cell types. The effect was immediate, with 50% loss of intracellular GSH within 2 h of treatment with DPI. The glutathione was quantitatively recovered in the extracellular medium, indicating that efflux was occurring. The loss of GSH was blocked with bromosulfophthalein, an inhibitor of the canalicular GSH transporters. We conclude that DPI induces a dramatic efflux of cellular GSH from T24 cells via a specific transport channel. This provides a potential mechanism for its proapoptotic effect, and it also has important implications for the regulation of glutathione homeostasis in cells.
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PMID:Diphenyleneiodonium triggers the efflux of glutathione from cultured cells. 1190 96

Phagocytosis of complement-opsonized targets is a primary function of neutrophils at sites of inflammation, and the clearance of neutrophils that have phagocytosed microbes is important for the resolution of inflammation. Our previous work suggests that phagocytosis leads to rapid neutrophil apoptosis that is inhibited by antibody to the beta2 integrin, Mac-1, and requires NADPH oxidase-derived reactive oxygen species (ROS) generated during phagocytosis. Here we report that phagocytosis-induced cell death (PICD) does not occur in Mac-1-deficient murine neutrophils, suggesting that PICD proceeds through a bona fide Mac-1-dependent pathway. A sustained, intracellular oxidative burst is associated with PICD. Furthermore, PICD does not require traditional death receptors, Fas, or tumor necrosis factor (TNF) receptor. TNF but not Fas synergizes with phagocytosis to enhance significantly PICD by increasing the oxidative burst, and this is Mac-1-dependent. Phagocytosis-induced ROS promote cleavage/activation of caspases 8 and 3, key players in most extrinsic ("death receptor") mediated pathways of apoptosis, and caspases 8 and 3 but not caspase 9/mitochondria, are required for PICD. This suggests that ROS target the extrinsic versus the intrinsic ("stress stimulus") apoptotic pathway. Phagocytosis also triggers a competing MAPK/ERK-dependent survival pathway that provides resistance to PICD likely by down-regulating caspase 8 activation. The anti-apoptotic factor granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly enhances ROS generation associated with phagocytosis. Despite this, it completely suppresses PICD by sustaining ERK activation and inhibiting caspase 8 activation in phagocytosing neutrophils. Together, these studies suggest that Mac-1-mediated phagocytosis promotes apoptosis through a caspase 8/3-dependent pathway that is modulated by NADPH oxidase-generated ROS and MAPK/ERK. Moreover, TNF and GM-CSF, likely encountered by phagocytosing neutrophils at inflammatory sites, exploit pro-(ROS) and anti-apoptotic (ERK) signals triggered by phagocytosis to promote or suppress PICD, respectively, and thus modulate the fate of phagocytosing neutrophils.
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PMID:Elucidation of molecular events leading to neutrophil apoptosis following phagocytosis: cross-talk between caspase 8, reactive oxygen species, and MAPK/ERK activation. 1273 63

Fas-Fas ligand (FasL)-dependent pathways exert a suppressive effect on inflammatory responses in immune-privileged organs. FasL expression in hepatic Kupffer cells (KC) has been implicated in hepatic immunoregulation. In this study, modulation of FasL expression of KC by endogenous gut-derived bacterial LPS and the role of reactive oxygen species (ROS) as potential mediators of FasL expression in KC were investigated. LPS stimulation of KC resulted in upstream ROS generation and, subsequently, increased FasL expression and consequent Jurkat cell (Fas-positive) apoptosis. The NADPH oxidase and xanthine oxidase enzymatic pathways appear to be major sources of this upstream ROS generation. Increased FasL expression was blocked by antioxidants and by enzymatic blocking of ROS generation. Exogenous administration of H2O2 stimulated KC FasL expression and subsequent Jurkat cell apoptosis. Intracellular endogenous ROS generation may therefore represent an important signal transduction pathway for FasL expression in KC.
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PMID:Lipopolysaccharides induced increases in Fas ligand expression by Kupffer cells via mechanisms dependent on reactive oxygen species. 1508 79

T cell receptor (TCR) stimulation induces rapid generation of reactive oxygen species, although the mechanisms for this are unclear. Here we found that T cells expressed a functional phagocyte-type nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. TCR crosslinking induced oxidase activation through the recruitment of preformed Fas ligand and Fas. TCR stimulation induced three separable events generating reactive oxygen species: rapid hydrogen peroxide production independent of Fas or NADPH oxidase; sustained hydrogen peroxide production dependent on both Fas and NADPH oxidase; and delayed superoxide production that was dependent on Fas ligand and Fas yet independent of NADPH oxidase. NADPH oxidase-deficient T cells showed enhanced activation of the kinase Erk and a relative increase in T helper type 1 cytokine secretion. Thus, mature T cells express a phagocyte-type NADPH oxidase that regulates elements of TCR signaling.
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PMID:T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. 1525 78

Since prolonged survival of activated neutrophils has an autotoxic potential, neutrophil apoptosis plays an important role in the rapid resolution of inflammation. Intravenous immunoglobulin (IVIG) preparations, which are beneficial therapeutic agents for the treatment of autoimmune diseases and systemic inflammatory diseases, have been reported to induce apoptosis of lymphocytes and endothelial cells in vitro. In the present study, we investigated whether IVIG may induce apoptosis of neutrophils cultured in vitro. After neutrophils prestimulated with or without lipopolysaccharide (LPS) were cultured in the presence or absence of IVIG, the number of apoptotic cells, intracellular H2O2 and GSH were measured by a flow cytometer. IVIG induced apoptosis of LPS-stimulated neutrophils dose dependently, but not in unstimulated neutrophils. Although anti-Fas monoclonal antibodies (mAbs) had no effect on the IVIG-induced apoptosis in the LPS-stimulated neutrophils, anti-Fc gamma receptor (Fc gammaR) II- and III-blocking mAbs significantly inhibited the IVIG-induced apoptosis. IVIG increased the production of intracellular H2O2, while it decreased the production of GSH, in the LPS-stimulated neutrophils. Furthermore, a specific NADPH oxidase inhibitor and anti-oxidants inhibited the IVIG-induced neutrophil apoptosis. Therefore, these findings indicate that IVIG preparations induce apoptosis of LPS-stimulated neutrophils and suggest that the IVIG-induced apoptosis may be mediated by an oxygen-dependent pathway via Fc gammaRII and III.
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PMID:Intravenous immunoglobulin preparations promote apoptosis in lipopolysaccharide-stimulated neutrophils via an oxygen-dependent pathway in vitro. 1586 8

CD95 ligand (CD95L) triggers a rapid formation of reactive oxygen species (ROS) as an upstream event of CD95 activation and apoptosis induction in rat hepatocytes. This ROS response was sensitive to inhibition by diphenyleneiodonium, apocynin, and neopterin, suggestive of an involvement of NADPH oxidases. In line with this, hepatocytes expressed mRNAs not only of the phagocyte gp91phox (Nox 2), but also of the homologs Nox 1 and 4 and Duox 1 and 2, as well as the regulatory subunit p47phox. gp91phox (Nox 2) and p47phox were also identified at the protein level in rat hepatocytes. CD95L induced within 1 min ceramide formation and serine phosphorylation of p47phox, which was sensitive to inhibitors of sphingomyelinase and protein kinase Czeta (PKCzeta). These inhibitors and p47phox protein knockdown inhibited the early CD95L-induced ROS response, suggesting that ceramide and PKCzeta are upstream events of the CD95L-induced Nox/Duox activation. CD95L also induced rapid activation of the Src family kinase Yes, being followed by activation of c-Src, Fyn, and c-Jun-N-terminal kinases (JNK). Only Yes and JNK activation were sensitive to N-acetylcysteine, inhibitors of NADPH oxidase, PKCzeta, or sphingomyelinase, indicating that the CD95L-induced ROS response is upstream of Yes and JNK but not of Fyn and c-Src activation. Activated Yes rapidly associated with the epidermal growth factor receptor (EGFR), which became phosphorylated at Tyr845 and Tyr1173 but not at Tyr1045. Activated EGFR then triggered an AG1478-sensitive CD95-tyrosine phosphorylation, which was a signal for membrane targeting of the EGFR/CD95 complex, subsequent recruitment of Fas-associated death domain and caspase 8, and apoptosis induction. All of these events were significantly blunted by inhibitors of sphingomyelinase, PKCzeta, NADPH oxidases, Yes, or EGFR-tyrosine kinase activity and after protein knockdown of either p47phox, Yes, or EGFR. The data suggest that CD95L-induced apoptosis involves a sphingomyelinase- and PKCzeta-dependent activation of NADPH oxidase isoforms, which is required for Yes/EGFR/CD95 interactions as upstream events of CD95 activation.
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PMID:Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. 1591 50

Prolonged stress has been shown to impair brain function and increase vulnerability to neuronal injury. To elucidate the in vivo response of neuronal cells to induced stress, we immobilized mice by binding their legs. Levels of reactive oxygen species (ROS) in the cerebral cortex were increased after stress induction. NADPH oxidase, interleukin-1beta (IL-1beta) and cyclooxygenase 2 mRNA (COX-2) expression levels were upregulated, and Fas levels were also increased. The increased expression of these factors was associated with neuronal death, which was confirmed by TUNEL and NeuN staining. OX42 staining was also evident around the TUNEL-stained lesions. From these findings, it appears that immobilization stress induces neuronal death in the mouse cerebral cortex, a process mediated by NADPH oxidase, IL-1beta, COX-2, ROS and Fas. However, this could be inhibited by pretreating the animals with antioxidants such as ebselen or pyrrolidine dithiocarbamate.
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PMID:Immobilization stress induces cell death through production of reactive oxygen species in the mouse cerebral cortex. 1620 91


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