Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.13.39 (NO synthase)
 15,778 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine peritoneal macrophages stimulated in vitro with killed Gram-positive bacteria Staphylococcus aureus or its membrane components in the presence of interferon-gamma (IFN-gamma) expressed high levels of nitric oxide (NO) synthase and produced large amounts of NO in a dose-dependent manner. This is not due to the contamination by Gram-negative endotoxin because the stimulatory activity was not affected by the addition of polymyxin B. The expression of the NO synthase and the synthesis of NO by macrophages stimulated with toxic shock syndrome toxin-1 (TSST), lipoteichoic acid (LTA) or killed whole S. aureus together with IFN-gamma was inhibited by the glucocorticoid, dexamethasone or by the specific inhibitor of NO synthesis, L-N-iminoethyl-ornithine (L-NIO). The exotoxins together with IFN-gamma also activated macrophages to kill the intracellular parasite Leishmania major. The leishmanicidal activity was completely inhibited by L-NIO.
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PMID:Induction of macrophage parasiticidal activity by Staphylococcus aureus and exotoxins through the nitric oxide synthesis pathway. 849 74

The role of microglia in host defense against Toxoplasma gondii is unknown. In the present study, we investigated the multiplication of T. gondii tachyzoites in murine microglial cell cultures. T. gondii multiplied readily in these cells; multiplication was prevented when microglia were activated with interferon-gamma plus lipopolysaccharide, a treatment that also upregulates nitric oxide (NO) synthase activity. Simultaneous treatment of microglial cell cultures with activation signals and the NO synthase inhibitor NG-monomethyl-L-arginine (NGMA) prevented the antitoxoplasmic activity. Transmission electron microscopic analysis demonstrated degenerative tachyzoites in activated microglia but not in control or NGMA groups. These findings support the view that the host defense function of activated microglia against T. gondii involves generation of the free radical NO.
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PMID:Activated microglia inhibit multiplication of Toxoplasma gondii via a nitric oxide mechanism. 851 93

We investigated the cytotoxic effects of various cytokines secreted by macrophages or T lymphocytes on luteal cells, and the role of nitric oxide (NO) produced by luteal cells in cytotoxic actions of cytokines. Mouse luteal cells were cultured in serum-free medium with interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 beta (IL-1 beta) alone, or with various combinations of these cytokines for 6 days. Cytotoxic actions of cytokines and NO production by luteal cells were evaluated by number of viable cells and the amount of nitrite and nitrate (stable metabolites of NO) in medium, respectively. IFN-gamma (1000 U/ml), TNF-alpha (3000 U/ml), or IL-1 beta (30 U/ml) alone, and the combination of TFN-alpha and IL-1 beta (10 U/ml) did not decrease number of viable cells and was without effects on NO production. The combination of IFN-gamma and IL-1 beta (10 U/ml) also did not decrease the number of viable cells, while it increased NO production a little but significantly. Combinations of INF-gamma and TNF-alpha, and IFN-gamma, TNF-alpha and IL-1 beta (10 U/ml) markedly decreased number of viable cells. The combination of IFN-gamma and TNF-alpha increased NO production a little but significantly, and the combination of three cytokines (IFN-gamma, TNF-alpha, and IL-1 beta) caused a greater increase in NO production. An NO synthase inhibitor, L-NG-monomethy-L-arginine (0.5 mM) or aminoguanidine (0.5 mM) abolished increases in NO production induced by combinations of IFN-gamma and TNF-alpha, and IFN-gamma, TNF-alpha and IL-1 beta completely without effects on number of viable cells. The present results indicate that combinations of cytokines including IFN-gamma and TNF-alpha induce death of cultured mouse luteal cells, and that the cytotoxic actions of these cytokines are independent of NO production by luteal cells.
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PMID:Cytotoxic actions of cytokines on cultured mouse luteal cells are independent of nitric oxide. 854 Dec 25

The injection of the 145-2C11 anti-CD3 MoAb in mice induces a polyclonal T cell activation resulting in the release of several cytokines, including interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). As these cytokines are known to be involved in the host defence against Trypanosoma cruzi, we measured serum levels of IFN-gamma and TNF-alpha after injection of the 145-2C11 MoAb in the course of experimental murine Chagas' disease. Compared with control mice, T. cruzi-infected BALB/c mice were found to be primed to secrete very high levels of IFN-gamma and TNF-alpha from the second and the first week of infection, respectively, up to the chronic phase. In vivo cell depletion experiments indicated that CD8+ T cells were responsible for these dramatic hyperproductions of IFN-gamma and TNF-alpha. While all control mice survived anti-CD3 MoAb injection, a high lethality rate was observed in T. cruzi-infected mice within 24 h after anti-CD3 MoAb challenge. Pretreatment with neutralizing anti-IFN-gamma MoAb or depletion of CD8+ T cell population dramatically decreased the mortality induced by anti-CD3 MoAb in T. cruzi-infected mice. Finally, we showed that anti-CD3 MoAb injection in T. cruzi-infected mice was followed by a massive release of nitric oxide (NO) metabolites, which was partially reduced by IFN-gamma or TNF-alpha neutralization. The administration of the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) before anti-CD3 MoAb challenge did not prevent and even enhanced lethality in T. cruzi-infected mice, suggesting that NO overproduction and lethal shock are not causally related. We conclude that injection of anti-CD3 MoAb in the course of experimental Chagas' disease induces a CD8+ cell-dependent shock mediated by IFN-gamma and TNF-alpha.
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PMID:Administration of anti-CD3 monoclonal antibody during experimental Chagas' disease induces CD8+ cell-dependent lethal shock. 856 5

The ability of lipid A and the antitumour compound, ONO-4007 (sodium2-deoxy-2-[3S-(9-phenylnonanoyloxy)tetradecanoyl] amino-3-O-(9phenylnonanoyl)-D-glucopyranose 4-sulphate) to induce nitric oxide (NO) synthase was investigated in vitro and in vivo, in comparison to the effects of lipopolysaccharide and di- and monophosphoryl lipid A. In J744.2 macrophages, lipopolysaccharide, di-and monophosphoryl lipid A and ONO-4007 (10(-9) - 10(-5) g/ml) alone, or in combination with interferon-gamma, induced NO synthase (order of potency: lipopolysaccharide > diphosphoryl lipid A > monophosphoryl lipid A > ONO-4007). ONO-4007 increased the activity of the inducible NO synthase in the lung of anesthetised rats (20% of the increased caused by bacterial lipopolysaccharide). Thus, ONO-4007 is a weak inducer of the inducible isoform of NO synthase in vitro and in vivo. The finding that di- and monophosphoryl lipid A also induce NO synthase indicates that the lipid A moiety of lipopolysaccharide contributes to the induction of NO synthase by lipopolysaccharide. The induction of NO synthase by ONO-4007, resulting in the formation of cytotoxic NO may contribute to the antitumour activity of the compound.
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PMID:Lipid A and the lipid A analogue anti-tumour compound ONO-4007 induce nitric oxide synthase in vitro and in vivo. 856 79

Inflammatory cytokines and nitric oxide (NO) are candidate mediators of pancreatic islet beta-cell destruction in insulin-dependent diabetes mellitus. In this study, we used a semiquantitative PCR assay to measure levels of messenger RNA (mRNA) expression of the inflammatory cytokines, interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha, and interferon-gamma (IFN gamma), and of the inducible form of NO synthase (iNOS) in mononuclear leukocytes isolated from pancreatic islets of autoimmune diabetes-prone nonobese diabetic (NOD) female mice. We found that mRNA levels of iNOS, IL-1 alpha, and IFN gamma in islet mononuclear leukocytes increased from 5 weeks of age to onset of diabetes ( > 13 weeks of age). To determine whether increased iNOS, IL-1 alpha, and IFN gamma mRNA expressions were related to diabetes development, we compared mRNA levels of these molecules in mononuclear leukocytes from islets of 12 week-old diabetes-prone NOD female mice and three groups of 12-week-old mice with low diabetes risk: NOD female mice injected with complete Freund's adjuvant at 4 weeks of age, NOD male mice, and BALB/c female mice that do not develop diabetes. We found that iNOS, IL-1 alpha, and IFN gamma mRNA levels were higher in mononuclear leukocytes from islets of diabetes-prone NOD female mice than in those from mice correlated with IL-1 alpha and IFN gamma mRNA levels. By using specific antibodies and immunohistochemical methods, we localized iNOS in macrophages as well as in beta-cells of islets from diabetes-prone NOD female mice. These findings suggest that IL-1 alpha and IFN gamma may promote islet beta-cell destruction at least in part by up-regulating iNOS expression an No production by both macrophages and beta-cells in the islets of autoimmune diabetes-prone NOD mice.
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PMID:Inducible nitric oxide synthase (iNOS) in pancreatic islets of nonobese diabetic mice: identification of iNOS- expressing cells and relationships to cytokines expressed in the islets. 861 52

The work reported here resolves, at the level of gene regulation, the controversy as to whether or not human monocytes/macrophages can produce nitric oxide (NO) when stimulated with lipopolysaccharide (LPS), with or without co-stimulation by interferon-gamma (IFN-gamma). Studies included structural comparison of the promoters for human and mouse inducible NO synthase (iNOS) genes, transfection and assay of human and mouse iNOS promoter regions in response to LPS +/- IFN-gamma, and electrophoretic mobility shift assays of kappa B response elements. Two explanations for hyporesponsiveness of the human iNOS promoter to LPS +/- IFN-gamma were found: (1) multiple inactivating nucleotide substitutions in the human counterpart of the enhancer element that has been shown to regulate LPS/IFN-gamma induced expression of the mouse iNOS gene; and (2) and absence of one or more nuclear factors in human macrophages (e.g., an LPS-inducible nuclear factor-kappa B/Rel complex), that is (are) required for maximal expression of the gene. The importance of resolution of this controversy is that future research in this area should be directed toward the understanding of alternative mechanisms that can result in the successful production of NO.
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PMID:Transcriptional basis for hyporesponsiveness of the human inducible nitric oxide synthase gene to lipopolysaccharide/interferon-gamma. 861 7

In the CNS, nitric oxide (NO) functions as both neuromodulator and neurotoxic agent. In vivo neuronal expression of NO synthase (NOS) has been attributed to constitutive NOS--both the neuronal and the endothelial types. The other class of NOS--the inducible NOS (iNOS)--is known to mediate toxic effects of NO in various tissues. In this study, we show for the first time that direct intracerebellar injection of endotoxin and cytokine (lipopolysaccharide and interferon-gamma) induced in vivo neuronal expression of the iNOS gene, as demonstrated by fluorescent in situ hybridization and immunohistochemical staining analyzed by confocal laser-scanning microscopy. This raises the possibility that neuronal iNOS might contribute significantly to the vulnerability of the brain to various insults.
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PMID:In vivo expression of inducible nitric oxide synthase in cerebellar neurons. 862 5

Nitric oxide (NO) functions as a pathophysiological mediator in mammalian tissues. Activated macrophages produce NO as a non-specific immune response directed against invading bacteria or micro-organisms. The same macrophages that initiate the production of NO also can be toxically affected by NO. Incubation of RAW 264.7 macrophages with lipopolysaccharide (LPS) and/or interferon-gamma (INF-gamma) induced the formation of NO by the activation of a cytokine-inducible NO synthase (NOS). The viability of these macrophages was inversely correlated with the formation of nitrite, a final NO-oxidation product measurable in the incubation medium. The addition of an NOS inhibitor, NG-monomethyl-L-arginine, diminished NO formation and preserved cell viability in a dose- and time-dependent fashion. Treatment of macrophages with ten cycles of non-lethal doses of LPS and INF-gamma, each followed by subculturing of the surviving cells, resulted in cell resistance to the NO toxic insult induced by LPS and INF-gamma. These resistant macrophages showed a 2-fold increase in the expression of the constitutive heat shock protein (HSC 70) which is known to be involved in protecting cells against the action of various metabolic insults. Our results establish a link between cell resistance to the toxic effects of NO, and the expression of heat shock proteins in RAW 264.7 macrophages.
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PMID:Heat shock proteins and macrophage resistance to the toxic effects of nitric oxide. 864 66

Nitric oxide (NO) is produced by a variety of human and animal cells and is involved in a broad array of physiological and pathophysiological processes. It can cause vasodilation, serve as a neurotransmitter, and have anti-neoplastic, anti-microbial, and anti-proliferative effects. In this study, we have demonstrated that fibroblasts derived from human skin spontaneously produce NO and that this production can be enhanced by stimulating the cells with interferon-gamma and lipopolysaccharide. The production of NO by human dermal fibroblasts can be blocked by NG-monomethyl-L-arginine (L-NMMA). The inhibitory effect of L-NMMA on NO production was restored by addition of L-arginine but not D-arginine. By measuring the rate of conversion of [14C]L-arginine to [14C]L-citrulline, we show that unstimulated cells expressed only Ca2+-dependent NO synthase (NOS) activity (1.36 +/- 0.57 pmol/mg/min; n = 4) whereas stimulated cells expressed both Ca2+-dependent (2.60 +/- 0.54 pmol/mg/min; n = 4) and -independent (1.59 +/- 0.14 pmol/mg/min; n = 4) NOS activities. With reverse transcription polymerase chain reaction (RT-PCR), the 422-bp RT-PCR product for human endothelial constitutive NOS and the 462-bp RT-PCR product for human hepatocyte inducible NOS were detected in proportion to the amount of mRNA-related RT-cDNA added to the reaction mixture. Further evidence by immunocytochemistry demonstrated that human dermal fibroblasts express both constitutive and inducible NOS proteins. These data collectively suggest that in addition to macrophages and other inflammatory cells, nitric oxide production by dermal fibroblasts could be important during the inflammatory stages of wound healing and possibly also in the later stages of proliferation and tissue remodeling after skin injury in humans.
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PMID:Human dermal fibroblasts produce nitric oxide and express both constitutive and inducible nitric oxide synthase isoforms. 864 70


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