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)

This review outlines evidence that IL-1, IL-2, and TNFs modulate neutrophil functions. These cytokines affect some or all of the following functions of the neutrophil: adherence, cell migration, respiratory burst, lysosomal enzyme release, and cell surface receptor expression. TNFs, especially TNF alpha, remains one of the most highly studied cytokine with respect to regulation of neutrophil function. TNFs are a direct stimuli for the neutrophil respiratory burst and weak stimuli of lysosomal enzyme release. The cytokines enhance cell adhesion and inhibit neutrophil migration. The TNFs augment the oxidative burst and lysosomal enzyme release response to a wide range of soluble and particulate cell stimuli. These changes in the cell seem to be closely correlated with the increased fungicidal, bactericidal, tumoricidal, and protozoacidal activity of the TNF-primed neutrophils. In contrast to TNFs, IL-1 and IL-2 inhibit neutrophil adherence, and this provides evidence that the cytokine family represents a regulatory system. Another form of regulation of TNF alpha and IL-1 neutrophil-activating activity is by the release of inhibitors to these cytokines (58). We have evidence which shows that the soluble TNF alpha inhibitor (a cleaved product of the TNF alpha receptor) (59) binds and inhibits TNF from activating and priming neutrophils (60). Priming of neutrophils by TNFs involves surface receptor binding but is independent of protein kinase C system, pertussis toxin-sensitive guanine nucleotide regulatory protein, and direct burst of respiratory activity. The translocation of cell surface receptors and constituents of the NADPH oxidase from stored vesicles may be the major mechanism of TNF-induced cell priming.
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PMID:Activation of neutrophils by interleukins-1 and -2 and tumor necrosis factors. 150 43

Reactive oxygen intermediates (ROIs) play an important role in inflammatory processes as mediators of injury and potentially in signal transduction leading to gene expression. Cyclooxygenase (COX) is a rate-limiting enzyme in prostanoid biosynthesis, and its recently cloned inducible form, COX-2, is induced by proinflammatory cytokines. This study linked ROIs to the signaling pathways that induce COX-2 expression. The hydroxyl radical scavengers DMSO (1%), as well as di- and tetramethylthiourea, inhibited IL-1-, TNF alpha-, and LPS-induced COX-2 expression in rat mesangial cells. The suppression of COX-2 mRNA expression correlated with the COX-2 protein level. In comparison with the prolonged induction of the inducible gene encoding protein-tyrosine phosphatase by hydrogen peroxide, the COX-2 gene was only transiently induced. Protein-tyrosine phosphatase is also induced by heat shock and chemical stress, whereas COX-2 is not. Superoxide was a more potent inducer for COX-2 than hydrogen peroxide. In addition, NADPH stimulated COX-2 expression, and an inhibitor of NADPH oxidase blocked COX-2 expression induced by TNF alpha. COX-2 and KC gene expression costimulated by IL-1 were inhibited differentially by the scavengers. These studies demonstrate that oxidant stress is a specific and important inducer of COX-2 gene expression. This induction may contribute to the deleterious amplification of prostanoids in inflammation and compound the direct effects of ROI production.
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PMID:Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-alpha, and lipopolysaccharide. 770 75

PMN obtained from asthmatic subjects demonstrate a heightened respiratory burst with increased superoxide generation compared to normals. This enhanced superoxide anion generation could be secondary to increased activity of the respiratory burst NADPH oxidase or diminished metabolism of superoxide via superoxide dismutase (SOD). The two forms of SOD expressed in PMN, CuZnSOD expressed constitutively in the cytosol and inducible mitochondrial MnSOD, were investigated in asthmatics. Resting PMN from asthmatics (N = 9) contained significantly less MnSOD activity compared to controls (0.46 +/- 0.16 vs. 0.79 +/- 0.17 units/10(7) PMN, respectively; P = 0.0002). As several cytokines including interleukins (IL) -1, -4, and -6 as well as granulocyte macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF) enhance the PMN respiratory burst and are synthesized in the asthmatic lung, their effects on PMN MnSOD activity were assayed. In contrast to its effects on lymphocytes, both IL-1 and IL-6 significantly inhibited in a dose-dependent fashion the induction of MnSOD in PMN from normals (0.42 +/- 0.12 and 0.45 +/- 0.05 units/10(7) PMN, respectively, at 10 units/ml of each cytokine; P = 0.02 compared to resting cells) but failed to further modulate MnSOD production in asthmatic PMN. IL-4 and GM-CSF had no effect on MnSOD production, and TNF effects could not be studied because of its effects on cell viability. There were no differences in the activity of CuZnSOD (N = 9) or NADPH oxidase (N = 4) in the two groups. Inhibition of MnSOD activity in PMN secondary to cytokine exposure in the asthmatic lung could explain, at least in part, the increased generation of superoxide from PMN obtained from asthmatics. This would promote the presence and severity of inflammation in the asthmatic lung. These data further support a role for IL-1 and IL-6 in allergic inflammation.
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PMID:Activities of superoxide dismutases and NADPH oxidase in neutrophils obtained from asthmatic and normal donors. 839 94

The expression of GADD45 was examined in cultured skin keratinocytes and in human skin in vivo following UV irradiation. Northern blot analysis revealed that UV-induced the expression of GADD45 (alpha, beta, gamma) in a time- and dose-dependent manner. Messenger RNA of GADD45 (alpha, beta, gamma) increased within 30 min, peaked at 4 h and remained elevated for at least 8 h following UV irradiation in vitro and in vivo. Maximal induction of GADD45alpha was approximately 5-fold compared to the level in sham-irradiated controls. Similarly H2O2 and IL-1 also induced GADD45alpha expression in cultured human keratinocytes. The kinetics of induction of GADD45alpha by H2O2, IL-1beta and UV were very similar. Interestingly, UV-induced GADD45alpha expression was inhibited by diphenylene iodonium (DPI), an inhibitor of NADPH oxidase, and antioxidant, N-acetyl-L-cysteine (NAC), indicating the involvement of reactive oxygen species in UV signaling. Previously we have shown that EGF receptor activation by UV is prerequisite for subsequent activation of NADPH oxidase and generation of reactive oxygen species. We therefore examined the effect of EGF receptor inhibitor on UV-induced GADD45alpha expression. Our results showed that PD168393, a potent EGF receptor inhibitor, blocked UV-induced GADD45alpha expression. Collectively, our data suggest that UV-induced GADD45alpha expression occur via an EGF receptor-mediated oxidative pathway sensitive to antioxidant regulation.
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PMID:UV-induced expression of GADD45 is mediated by an oxidant sensitive pathway in cultured human keratinocytes and in human skin in vivo. 1107 29

We studied the mechanism of the superoxide generation system in indomethacin-induced gastric mucosal injury. First, 10 mM indomethacin had no direct effect on xanthine oxidase (XOD) activity. Next, we found that NADPH oxidase activity in polymorphonuclear leukocytes (PMN) of peripheral blood was significantly increased 6 h after administration of indomethacin. This phenomenon was inhibited by the injection of the NADPH oxidase inhibitor, diphenylene iodonium chloride (DIC). Activation of NADPH oxidase caused the component, p47phox to be translocated to the plasma membrane. Since indomethacin did not directly activate NADPH oxidase, we sought another route of activation of PMN. As IL-1 and TNF alpha play in the inflammation, we examined these cytokines in this study. TNF alpha was not detected but IL-1 was increased significantly 30 min after administration of indomethacin.
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PMID:Mechanism of superoxide generation system in indomethacin-induced gastric mucosal injury in rats. 1121 83

Lipopolysaccharide (LPS) stimulates macrophages to release inflammatory cytokines, interleukin-1 beta (IL-1), and tumor necrosis factor (TNF). LPS-induced TNF suppresses scavenger receptor functions in macrophages (van Lenten, B. J., and Fogelman, A. M. (1992) J. Immunol. 148, 112-116), which is regulated by TNF-mediated protein kinases (Hsu, H. Y., and Twu, Y. C. (2000) J. Biol. Chem. 275, 41035-41048). To examine the molecular mechanism for LPS induction of IL-1 in macrophages, we demonstrated that LPS quickly stimulated reactive oxygen species (ROS), and 3 h later induced prointerleukin-1 beta (pro-IL-1, precursor of IL-1) production and IL-1 secretion. LPS stimulated pro-IL-1 message/protein between 3 and 10 h; however, there was a 40% reduction of pro-IL-1 in preincubation of the antioxidant, N-acetylcysteine (NAC). Moreover, NAC moderated LPS-induced IL-1 secretion partially via interleukin 1-converting enzyme. The maximal activity of LPS-induced ERK, JNK, and p38 was 12- (30 min), 5- (30 min), and 16-fold (15 min), respectively. In contrast, NAC reduced ERK activity to 60% and decreased p38 activity to the basal level, but JNK activity was induced 2-fold. Furthermore, the pharmacological antagonists LY294002, SB203580, curcumin, calphostin C, and PD98059 revealed the diverse roles of LPS-mediated protein kinases in pro-IL-1. On the other hand, NAC and diphenyleneiodonium chloride partially inhibited LPS-induced Rac activity and protein-tyrosine kinase (PTK), indicating that LPS-mediated ROS and NADPH oxidase correspond to Rac activation and IL-1 expression. Our findings establish for the first time that LPS-mediated PTK/phosphatidylinositol 3-kinase/Rac/p38 pathways play a more important role than pathways of PTK/PKC/MEK/ERK and of PTK/phosphatidylinositol 3-kinase/Rac/JNK in the regulation of pro-IL-1/IL-1. The findings also further elucidate the critical role of LPS-mediated ROS in signal transduction pathways. Our results suggest that understanding LPS-transduced signals in IL-1 induction upon the antibacterial action of macrophages should provide a therapeutic strategy for aberrant inflammatory responses leading to severe cellular injury or concurrent multiorgan septic damage.
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PMID:Lipopolysaccharide-mediated reactive oxygen species and signal transduction in the regulation of interleukin-1 gene expression. 1194 May 70

Activation of endothelial cell NF-kappaB by interleukin (IL)-1 constitutes an event critical to the progression of the innate immune response. In this context, oxidants have been associated with NF-kappaB activation, although the molecular source and mechanism of targeting have remained obscure. We found that RelA, essential for NF-kappaB activation by IL-1, was associated with the NADPH oxidase adapter protein p47(phox) in yeast two-hybrid, coprecipitation, and in vitro binding studies. RelA and p47-GFP also colocalized in endothelial cells in focal submembranous dorsoventral protrusions. Overexpression of p47(phox) synergized with IL-1beta in the activation of an artificial kappaB-luciferase reporter and specifically augmented IL-1beta-induced RelA transactivation activity. p47(phox) overexpression also greatly increased IL-1beta-stimulated RelA phosphorylation, whereas it had no effect on I-kappaB degradation or on RelA nuclear translocation or kappaB binding. The tandem SH3 domains of p47(phox) were found to associate with a proline-rich mid-region of RelA (RelA-PR) located between the Rel homology and transactivation domains. The RelA-PR peptide blocked interaction of p47(phox) and RelA, and ectopic expression of RelA-PR abrogated IL-1beta-induced transactivation of the NF-kappaB-dependent E-selectin promoter. Further, suppression of NADPH oxidase function through the inhibitor diphenylene iodonium, the superoxide dismutase mimetic Mn(III) tetrakis(4-benzoic acid)porphyrin (MnTBAP), or expression of a dominant interfering mutant of a separate NADPH oxidase subunit (p67(V204A)) decreased IL-1beta-induced E-selectin promoter activation, suggesting that p47(phox) facilitates NF-kappaB activation through linkage with the NADPH oxidase. IL-1beta rapidly increased tyrosine phosphorylation of IL-1 type I receptor-associated proteins, suggesting that oxidants may operate through inactivation of local protein-tyrosine phosphatases in the proximal IL-1beta signaling pathway leading to RelA activation.
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PMID:p47phox participates in activation of RelA in endothelial cells. 1261 29

Phosphorylation of p47(phox) is a key event in NADPH oxidase activation. We examined the ability of proinflammatory cytokines such as TNFalpha, IL-1, and G-CSF to induce this process compared with GM-CSF. Only TNF-alpha and GM-CSF induced a clear p47(phox) phosphorylation. This phosphorylation was time dependent and reached its maximum at 20 min. Two-dimensional phosphopeptide mapping of p47(phox) phosphorylated in neutrophils primed with TNF-alpha revealed partial phosphorylation of p47(phox) on the same peptide as for GM-CSF. Neutrophil incubation with TNF-alpha and subsequent addition of the chemotactic peptide fMLP resulted in more intense phosphorylation of p47(phox) sites than with each reagent alone. A neutralizing Ab against the p55 TNF receptor, contrary to a neutralizing Ab against the p75 TNF receptor, inhibited TNF-alpha-induced p47(phox) phosphorylation. Neutrophil treatment with both TNF-alpha and GM-CSF resulted in more intense phosphorylation of the same p47(phox) peptide observed with each cytokine alone, suggesting that they engaged pathways converging on common serines. This additive effect was also obtained on the priming of NADPH oxidase activity. The use of protein kinase inhibitors pointed to the involvement of a protein tyrosine kinase, but not protein kinase C. These findings show that TNF-alpha, via its p55 receptor, induces a protein tyrosine kinase-dependent selective phosphorylation of p47(phox) on specific serines. The ability of TNF-alpha and GM-CSF, two different cytokines with two different receptors to induce this specific p47(phox) phosphorylation, suggests that this event could be a common element of the priming of neutrophils by TNF-alpha and GM-CSF.
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PMID:TNF-alpha induces phosphorylation of p47(phox) in human neutrophils: partial phosphorylation of p47phox is a common event of priming of human neutrophils by TNF-alpha and granulocyte-macrophage colony-stimulating factor. 1453 Mar 65

Cultured human THP-1 monocytes were exposed to serial concentrations of gemifloxacin over 4 h after pre-stimulation with zymogen A for 1 h or Staphylococcus aureus for 2 h. The following parameters were assessed: pH, phagocytosis, c-AMP, NO, TNFalpha, IL-1, IL-6, IL-8 and H2O2 levels, enzyme activities of protein kinase C, NADPH oxidase, SOD, gluthathion reductase, NAG and cathepsin D as well as lipid peroxidation. The reversiblity of these changes was determined in the presence of known blockers of the phagocytic process. The effects of gemifloxacin on DNA synthesis and killing of S. aureus was assessed in bacteria alone and in those bacteria phagocytosed by THP-1 monocytes over 24 h. Gemifloxacin in stimulated THP-1 monocytes over the first 30 min caused an increase in c-AMP, NO, H2O2 and TNFalpha levels and protein kinase C, NADPH oxidase, glutathione reductase, NAG and cathepsin D activities. The pH became more acidic and phagocytosis was stimulated. These parameters were reversed at 1 h and continued to decline until 4 h. Lipid peroxidation was at the highest levels at 1 h and IL-8 levels at 2 h. DNA synthesis and bacterial growth were suppressed at 2 h in both S. aureus alone and bacteria phagocytosed by THP-1 monocytes. These effects were at a higher magnitude at 24 h. Gemifloxacin initiates a phagocyticidal effect of THP-1 monocytes at an early time of 30 min which plays a role in killing bacteria but a higher magnitude of killing of bacteria occurs later by a standard static mechanism. This early action of gemifloxacin should decrease the spread of infection and the inflammatory response since the tissue destruction process was attenuated at 4 h.
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PMID:In vitro anti-inflammatory effects and immunomodulation by gemifloxacin in stimulated human THP-1 monocytes. 1549 55

Monocyte chemoattractant protein-1 (MCP-1) is expressed in vascular endothelial cells of inflamed gingival tissues and plays an important role in periodontal pathogenesis. Endothelial cells produce high levels of MCP-1 in response to Porphyromonas gingivalis, an important periodontal pathogen. The present study investigated the mechanisms involved in MCP-1 production by human umbilical vein endothelial cells (HUVEC) following infection with P. gingivalis. In contrast to P. gingivalis, Bacteroides forsythus only weakly stimulated MCP-1 production while Treponema denticola could not induce MCP-1 in HUVEC. The MCP-1 production was independent of endogenous interleukin (IL)-1alpha as IL-1 receptor antagonist treatment did not reduce MCP-1 production by P. gingivalis. Meanwhile, antioxidant treatment and inhibition of NAD(P)H oxidase significantly reduced MCP-1 production. Pharmacological inhibition of p38 mitogen-associated protein (MAP) kinase, c-Jun N-terminal kinase (JNK), nuclear factor-kappaB (NF-kappaB) or activator protein-1 (AP-1) also substantially attenuated P. gingivalis-induced MCP-1 expression by HUVEC. Indeed, activation of NF-kappaB and AP-1 was observed in P. gingivalis-infected HUVEC. These results suggest that MCP-1 expression is upregulated in P. gingivalis-infected endothelial cells via reactive oxygen species, p38 MAP kinase, JNK, NF-kappaB, and AP-1.
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PMID:Mechanisms of Porphyromonas gingivalis-induced monocyte chemoattractant protein-1 expression in endothelial cells. 1578 May 78


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