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

Production of reactive oxygen intermediates (ROI) by the NADPH oxidase of neutrophils is a major mechanism of bacterial killing and, in pathologic circumstances, tissue damage. Integrins and selectins participate in neutrophil adhesion but may also play a role in intracellular signaling. The role of L-selectin in ROI production and Ca2+ signaling in suspended neutrophils was examined using the DREG series of anti-L-selectin antibodies. NADPH oxidase activation was assessed in three ways: H2O2 production using either scopoletin or dihydrorhodamine and O2- production using cytochrome c. Alterations in [Ca2+]i were measured using Fura 2-AM and fluorescence spectrophotometry. Cross-linking of L-selectin with DREG and 2 degrees antibody did not trigger production of H2O2 by itself but significantly enhanced the subsequent response to two soluble activating agents; the formyl peptide formyl-Met-Leu-Phe (fMLP) and tumor necrosis factor (TNF). Potentiation of the oxidative burst was observed using F(ab')2 fragments but not with irrelevant antibodies and was observed whether 2 degrees antibody was added before or after fMLP. Cross-linking of L-selectin also triggered a rise in [Ca2+]i, due, in part, to release from intracellular stores. The intracellular Ca2+ chelator BAPTA blocked both the rise in [Ca2+]i and the potentiation of the oxidative burst in response to fMLP or TNF. We conclude that cross-linking of L-selectin induces intracellular signals, including release of Ca2+, which may contribute to potentiation of the oxidative burst.
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PMID:Potentiation of the oxidative burst of human neutrophils. A signaling role for L-selectin. 751 34

Phagocytosis and oxidative burst are critical host defense mechanisms in which neutrophils clear invading pathogens. Clearing phagocytic neutrophils by triggering apoptosis is an essential process for controlling inflammation. This study elucidates how various exercise bouts with/without hypoxia affected neutrophil bactericidal activity and subsequent apoptosis in humans. Fifteen sedentary males performed six distinct experimental tests in an air-conditioned normobaric hypoxia chamber: two normoxic exercises [strenuous exercise (SE; up to maximal O2 consumption) and moderate exercise (ME; 50% maximal O2 consumption for 30 min) while exposed to 21% O2], two hypoxic exercises (ME for 30 min while exposed to 12% and 15% O2), and two hypoxic exposures (resting for 30 min while exposed to 12% and 15% O2). The results showed that 1) plasma complement-C3a desArg/C4a desArg/C5a concentrations were increased, 2) expressions of L-selectin/lymphocyte functin-associated antigen-1/Mac-1/C5aR on neutrophils were enhanced, 3) phagocytosis of neutrophils to Esherichia coli and release of neutrophil oxidant products by E. coli were elevated, and 4) E. coli-induced phosphotidylserine exposure or caspase-3 activation of neutrophils were promoted immediately and 2 h after both 12% O2 exposure at rest and with ME as well as normoxic SE. Although neither normoxic ME nor breathing 15% O2 at rest influenced these complement- and neutrophil-related immune responses, ME at both 12% and 15% O2 resulted in enhanced complement activation in the blood, expressions of opsonic/complement receptors on neutrophils, or the bactericidal activity and apoptosis of neutrophils. Moreover, the increased neutrophil oxidant production and apoptosis by normoxic SE and hypoxic ME were ameliorated by treating neutrophils with diphenylene iodonium (a NADPH oxidase inhibitor). Therefore, we conclude that ME at 12-15% O2 enhances bactericidal capacity and facilitates the subsequent apoptosis of neutrophils.
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PMID:Systemic hypoxia enhances exercise-mediated bactericidal and subsequent apoptotic responses in human neutrophils. 1964 31

Migration of naive CD4(+) T lymphocytes into lymphoid tissue is essential for their activation and subsequent roles in adaptive immunity. The adhesion molecule L-selectin (CD62L), critical for this process, is highly expressed on naive CD4(+) T lymphocytes and is downregulated upon T lymphocyte activation. We demonstrate protein expression of P2X7R on naive CD4(+) T lymphocytes and show functional channel activity in whole-cell patch clamp recordings. CD62L downregulation occurs rapidly in response to extracellular ATP, a process that is blocked by selective antagonists of P2X7R. This loss of surface CD62L expression was not associated with externalization of phosphatidylserine. While investigating the mechanisms for this process, we revealed that pharmacological modulation of mitochondrial complex I or III, but not inhibition of NADPH oxidase, enhanced P2X7R-dependent CD62L downregulation by increasing ATP potency. Enhanced superoxide generation in the mitochondria of rotenone- and antimycin A-treated cells was observed and may contribute to the enhanced sensitivity of P2X7R to ATP. P2X7R-dependent exposure of phosphatidylserine was also revealed by preincubation with mitochondrial uncouplers prior to ATP treatment. This may present a novel mechanism whereby P2X7R-dependent phosphatidylserine exposure occurs only when cells have enhanced mitochondrial reactive oxygen species generation. The clearance of apoptotic cells may therefore be enhanced by this mechanism which requires functional P2X7R expression.
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PMID:Mitochondrial superoxide generation enhances P2X7R-mediated loss of cell surface CD62L on naive human CD4+ T lymphocytes. 2331 34

Neutrophils destroy invading microorganisms by phagocytosis by bringing them into contact with bactericidal substances, among which ROS are the most important. However, ROS also function as important physiological regulators of cellular signaling pathways. Here, we addressed the involvement of oxygen derivatives in the regulation of human neutrophil rolling, an essential component of the inflammatory response. Flow experiments using dihydroethidium-preloaded human neutrophils showed that these cells initiate an early production of intracellular ROS during the rolling phase of the adhesion cascade, a phenomenon that required cell rolling, and the interaction of the chemokine receptor CXCR2 with their ligand CXCL8. Flow cytometry experiments demonstrated that L-selectin shedding in neutrophils is triggered by ROS through an autocrine-paracrine mechanism. Preincubation of neutrophils with the NADPH oxidase complex inhibitor diphenyleniodonium chloride significantly increased the number of rolling neutrophils on endothelial cells. Interestingly, the same effect was observed when CXCL8 signaling was interfered using either a blocking monoclonal antibody or an inhibitor of its receptor. These findings indicate that, in response to CXCL8, neutrophils initiate ROS production during the rolling phase of the inflammatory response. This very early ROS production might participate in the modulation of the inflammatory response by inducing L-selectin shedding in neutrophils.
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PMID:L-selectin expression is regulated by CXCL8-induced reactive oxygen species produced during human neutrophil rolling. 3044 3