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:1.6.99.6 (NADPH oxidase)
10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Reactive oxygen species (ROS) play an important but not yet fully defined role in the expression of inflammatory genes such as monocyte chemoattractant protein (MCP)-1. We used complementary molecular and biochemical approaches to explore the roles of specific ROS and their molecular linkage to inflammatory signaling in endothelial cells. Adenovirus-mediated expression of superoxide dismutase and catalase inhibited TNF-alpha-induced MCP-1 gene expression, suggesting important roles of superoxide (O(2)(-).) and H(2)O(2) in MCP-1 gene activation. In addition, the iron chelator 1,2-dimethyl-3-hydroxypyridin-4-one and the hydroxyl radical scavengers dimethylthiourea and dimethyl sulfoxide inhibited TNF-alpha-induced MCP-1 expression, suggesting important roles of iron and hydroxyl radicals in inflammatory signal activation. In contrast, scavenging of peroxynitrite with 5,10,15,20-tetrakis-(4-sulfonatophenyl)prophyrinato iron (III) chloride had no effect on TNF-alpha-induced MCP-1 expression. Inhibition of NADPH oxidase, the major oxidase responsible for O(2)(-). generation, with diphenylene iodonium suppressed TNF-alpha-induced MCP-1 mRNA accumulation. Rac1 is an upstream signaling molecule for the activation of NADPH oxidase and O(2)(-). generation. Expression of dominant negative N17Rac1 by adenovirus suppressed TNF-alpha-induced MCP-1 mRNA levels and MCP-1 protein secretion. Expression of N17Rac1 inhibited TNF-alpha-induced MCP-1 and NF-kappaB transcriptional activity. These data suggest that ROS such as superoxide and H(2)O(2) derived from Rac1-activated NADPH oxidase mediate TNF-alpha-induced MCP-1 expression in endothelial cells.
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PMID:Superoxide, H2O2, and iron are required for TNF-alpha-induced MCP-1 gene expression in endothelial cells: role of Rac1 and NADPH oxidase. 1457 80

We examined the role of redox signaling generated by NADPH oxidase in activation of NF-kappaB and host defense against Pseudomonas aeruginosa pneumonia. Using mice with an NF-kappaB-driven luciferase reporter construct (HIV-LTR/luciferase (HLL)), we found that intratracheal administration of P. aeruginosa resulted in a dose-dependent neutrophilic influx and activation of NF-kappaB. To determine the effects of reactive oxygen species generated by the NADPH oxidase system on activation of NF-kappaB, we crossbred mice deficient in p47(phox) with NF-kappaB reporter mice (p47(phox-/-)HLL). These p47(phox-/-)HLL mice were unable to activate NF-kappaB to the same degree as HLL mice with intact NADPH oxidase following P. aeruginosa infection. In addition, lung TNF-alpha levels were significantly lower in p47(phox-/-)HLL mice compared with HLL mice. Bacterial clearance was impaired in p47(phox-/-)HLL mice. In vitro studies using bone marrow-derived macrophages showed that Toll-like receptor 4 was necessary for NF-kappaB activation following treatment with P. aeruginosa. Additional studies with macrophages from p47(phox-/-) mice confirmed that redox signaling was necessary for maximal Toll-like receptor 4-dependent NF-kappaB activation in this model. These data indicate that the NADPH oxidase-dependent respiratory burst stimulated by Pseudomonas infection contributes to host defense by modulating redox-dependent signaling through the NF-kappaB pathway.
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PMID:p47phox deficiency impairs NF-kappa B activation and host defense in Pseudomonas pneumonia. 1473 63

Pigment epithelium-derived factor (PEDF) has recently been shown to be involved in the pathogenesis of proliferative diabetic retinopathy. Atherosclerosis is an inflammatory-fibroproliferative disease as well. Oxidative stress plays a major role in retinopathy and atherosclerosis. Accordingly, we investigated effects of PEDF on reactive oxygen species (ROS) generation, NF-kappaB activation and interleukin (IL)-6 expression in TNF-alpha-exposed HUVEC. TNF-alpha significantly increased intracellular ROS generation, which was completely blocked by PEDF or diphenylene iodonium, an inhibitor of NADPH oxidase. Further, PEDF completely prevented the TNF-alpha-induced increase in NADPH oxidase activity. PEDF or an antioxidant, N-acetylcysteine, significantly inhibited the TNF-alpha-induced NF-kappaB activation. PEDF inhibited TNF-alpha-induced expression of IL-6 at both mRNA and protein levels. Moreover, TNF-alpha downregulated PEDF mRNA levels. Ligand blot analysis revealed that HUVEC possessed a membrane protein with binding affinity for PEDF. The results demonstrated that PEDF inhibited TNF-alpha-induced NF-kappaB activation and subsequent IL-6 overexpression in HUVEC by suppressing NADPH oxidase-mediated ROS generation. Our present study suggests that PEDF may play an important role in the development and progression of atherosclerosis.
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PMID:Pigment epithelium-derived factor inhibits TNF-alpha-induced interleukin-6 expression in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. 1527 19

Myeloperoxidase (MPO), next to the NO synthase2 (NOS2), and NADPH oxidase, is the key enzyme of the oxidative burst responsible for the antimicrobial immunity. Because MPO participates in the eradication of Mycobacterium tuberculosis in the in vitro model and the extracellular enzyme may activate cells to cytokine synthesis, we investigated the changes in the enzyme concentration in serum of patients with active pulmonary tuberculosis (TB) and correlations between MPO and TNF-alpha, IFN-gamma, and IL-12. To our knowledge, our study is the first to indicate the involvement of MPO during active TB which manifested itself in the significant increase in serum concentration. The statistically significant elevation of TNF-alpha and IL-12 was also noticed in serum of the TB positive group. The statistical analysis revealed no correlation between the cytokine and MPO production in the studied cases. However, the increase in TNF-alpha and IL-12 serum concentration with simultaneous elevation of serum MPO in the group of the highest enzyme concentration may imply that correlation between the enzyme and the cytokines should not be excluded. Our study suggests possible involvement of MPO in the antituberculous, immunological response, and implies its connection with TNF-alpha and IL-12 activation.
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PMID:Study on myeloperoxidase role in antituberculous defense in the context of cytokine activation. 1537 10

Cigarette smoke (CS)-induced emphysema is attributable to matrix metalloproteinase-12 (MMP-12) in mice, however, a relationship between CS and MMP-12 is absent in human emphysema. Here, we show that cigarette smoke condensate (CSC) induces MMP-12 gene expression in airway-like epithelia through a hydrogen peroxide (H(2)O(2))-dependent pathway involving NADPH oxidase, AP-1, and TNF-alpha. Cigarette smoke condensate-induced H(2)O(2) production and MMP-12 gene expression were inhibited by apocynin, a specific inhibitor of NADPH oxidases, while 3-aminobenzamide, an inhibitor of AP-1, attenuated CSC-induced MMP-12 gene expression. Messenger RNAs encoding phagocytic NADPH oxidase components and a homologue of p67phox, p51 (NOXA1), were detected, while mRNA of dual oxidase (Duox)1 was unchanged by CSC. Enbrel, an inhibitor of TNF-alpha function, reduced CSC-induced H(2)O(2) production and MMP-12 expression. These findings provide novel evidence of a direct relationship between CS exposure and MMP-12 in human airway epithelia and suggest several targets for modulation of this potentially pathogenic pathway.
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PMID:Cigarette smoke condensate induces MMP-12 gene expression in airway-like epithelia. 1578 Dec 50

The therapeutic efficacy in the treatment of metastatic cancer with high doses of interleukin-2 (IL-2) has been limited by the onset of vascular leak syndrome (VLS) and related toxicities. VLS is characterized by an increase in vascular permeability and severe hypotension resulting in interstitial edema and organ failure. This study explores the protective effects of histamine dihydrochloride (HDC) against IL-2-induced toxicities in mice. Treatment with HDC administered before or after IL-2 (1.25 x 10(6) IU, BID) was shown to protect mice from VLS-related toxicities and mortality in a dose-dependent manner. Survival rates when HDC was added were 56, 75 and 81% at doses of 0.47, 4.7 and 47.0 mg/kg, respectively, compared to 42% survival with IL-2 alone. HDC protected against IL-2-induced macroscopic pulmonary lesions, reduced edema (up to 62% reduction in lung wet/dry weight ratio) and reduced capillary leakage into the lungs as measured by a reduction in Evans Blue dye content. In addition, the systemic effect on serum cytokine levels showed that HDC only moderately lowered IL-2 induced IFN-gamma, IL-6, IL-10, IL-18 and TNF-alpha. Serum levels of IL-1beta, IL-4 and IL-12 were not measurably induced by IL-2 treatment. HDC modulates many cellular functions including regulating cytokines and blocking immune-suppression caused by reactive oxygen species (ROS) generated by the NADPH oxidase. However, the protective effect of HDC on alleviating IL-2-induced pulmonary edema was not related to ROS inhibition. Our data indicate that HDC treatment improves survival and protects against IL-2 induced VLS independent of ROS regulation in mice.
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PMID:Histamine improves survival and protects against interleukin-2-induced pulmonary vascular leak syndrome in mice. 1582 Apr 45

Insulin resistance and central obesity are often associated with hypertension. The metabolic syndrome is a cluster of these common clinical disorders, and is related with an increased risk for cardiovascular diseases. A number of pro-inflammatory cytokines derived from adipose tissues have been thought to contribute to the development of insulin resistance and accelerated atherosclerosis. Among them, TNF-alpha has been most widely studied; it not only suppresses the insulin signaling, but also elicits vascular inflammation. Indeed, inhibition of TNF-alpha was found to improve insulin resistance in obese rats and reduce the progression of atherosclerosis in apolipoprotein E knockout mice, respectively. These observations demonstrate that TNF-alpha could play a central role in the pathogenesis of insulin resistance and accelerated atherosclerosis in the metabolic syndrome. Considering that the primary goals of treatment for hypertensive patients with the metabolic syndrome are prevention of the development of diabetes and cardiovascular events, anti-hypertensive drugs that have abilities to block the TNF-alpha signaling would be desirable as a first-line therapy for these patients. In the process of the search for such a unique anti-hypertensive drug, we have recently found that azelnidipine, a newly developed and commercially used long-acting dihydropyridine-based calcium antagonist (DHP), inhibited TNF-alpha-induced activator protein-1 activation and interleukin-8 expression in human umbilical vein endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. The concentration of azelnidipine that was found effective in these in vitro-experiments is well within the therapeutic range. Since endothelial cells do not possess voltage-operated L-type calcium channels, these observations suggest that the beneficial effects of azelnidipine are not likely due to calcium channel blocking property, but due to its unique anti-oxidative ability. Furthermore, we have very recently found that serum levels of monocyte chemoattractant protein-1, a biomarker for subclinical atherosclerosis, were significantly decreased by the treatment of azelnidipine in patients with essential hypertension. In this paper, we would like to hypothesize that due to its unique TNF-alpha signal modulatory, anti-oxidative property, azelnidipine may be a promising DHP that targets diabetes and cardiovascular diseases in hypertensive patients with the metabolic syndrome.
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PMID:Unique atheroprotective property of azelnidipine, a dihydropyridine-based calcium antagonist. 1589 34

AT(1) double receptor (AT(1A) and AT(1B)) knockout mice have lower blood pressure, impaired growth, and develop early renal microvascular disease and tubulointerstitial injury. We hypothesized that there would be an increased expression of vasoactive, profibrotic, and inflammatory mediators expressed in the kidneys of AT(1) double-knockout mice. We examined the renal expression of various mediator systems in control (n = 6) vs. double-knockout mice (n = 6) at 3-5 mo of age by real-time PCR, immunohistochemistry, and Western blot analysis. AT(1) double-knockout mice show activation of Th1-dependent pathways (with increased expression of IFN-alpha, IL-2 mRNA) with increased expression of both monocyte (MCP-1 mRNA) and T cell (RANTES mRNA) chemokines, infiltration of CD4(+) and CD11b(+) cells, increased fibrosis-associated mediators (CTGF, TGF-beta and TNF-alpha mRNA) and extracellular matrix (collagens I and III mRNA and protein) deposition compared with controls (P < 0.05 for all markers). These changes were associated with increased mRNA expression of endothelin (ET)-1 and ET-A receptor (P < 0.05), cyclooxygenase (COX)-2/TXA2 synthase (P < 0.05), NADPH oxidase (p40-phox, p67-phox, P < 0.05) and iNOS and nNOS (P < 0.05). COX-2 and nNOS protein were also increased in the kidneys of AT(1) double-knockout mice by Western blot analysis (P < 0.05). Although renin and angiotensinogen mRNA expression were increased in the knockout mice, AT(2) receptor mRNA expression was not significantly different from wild-type mice. In conclusion, the absence of the AT(1) receptor is associated with marked renal alterations in vasoactive, profibrotic, and immune mediators with an inflammatory pattern favoring a Th1 phenotype.
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PMID:Th1 inflammatory response with altered expression of profibrotic and vasoactive mediators in AT1A and AT1B double-knockout mice. 1592 10

Sepsis is a complex clinical syndrome that results from a harmful host response to infection, in which foreign bacteria and lipopolysaccharide (LPS) are potent activators of different immune cells, including monocytes and macrophages. To date, there are currently few effective adjuvant therapies in clinical use except activated protein C focusing on the coagulation system. Mastoparans (MPs) are wasp venom cationic amphiphilic tetradecapeptides; these are capable of modulating various cellular activities, including stimulation of GTP-binding protein, phospholipase C and can bind to a phospholipid bilayer. Masroparan-1 (MP-1, INLKAIAALAKKLL-NH2), a tetradecapeptide toxin isolated from hornet venom, was synthesized chemically. In this study, Escherichia coli 25922 (E. coli 25922) and LPS were used to induce sepsis in an animal model. We found that MP-1 treatment at 3 mg/kg protected mice from otherwise lethal bacteria and LPS challenges. MP-1 has antibacterial capabilities against Gram-negative and Gram-positive bacteria. Its antibacterial action against E. coli may result from the destruction of bacterial membrane structures. In addition, treatment of murine peritoneal macrophages with MP-1 potently inhibited the respiratory burst. This effect maybe related to an inhibition of NADPH oxidase in the membrane. Furthermore, MP-1, bound with high-affinity to LPS and lipid A with dissociation equilibrium constants of 484 and 456 nM, respectively, and neutralized LPS in a dose-dependent manner. MP-1 also significantly reduced the expression of TLR4, TNF-alpha and IL-6 mRNA and the release of cytokines in LPS-stimulated murine peritoneal macrophages. Our results shows that the MP-1-mediated protection of mice from lethal challenge by live bacteria and LPS was associated with its bactericidal action and inhibition of inflammatory responses by macrophages to both bacteria and LPS (the release of cytokines and reactive oxygen species).
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PMID:A synthesized cationic tetradecapeptide from hornet venom kills bacteria and neutralizes lipopolysaccharide in vivo and in vitro. 1593 30


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