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)

Nitric oxide (NO) is a short-lived diffusable molecule now believed to participate in multiple physiologic functions in the CNS including neurotransmission and the maintenance of vascular tone. Previously, we reported that cell lines obtained by retroviral immortalization of tissue macrophages (M phi) could be induced to synthesize nitrite (NO2-), a stable end product of the NO synthetic pathway. We have further characterized the induction and activity of this pathway in a panel of seven microglial clones derived from primary embryonic mouse brain cultures. Like M phi, these clones were found to release high levels of NO2- in response to recombinant interferon-gamma (rIFN-gamma) as a priming signal together with either bacterial lipopolysaccharide (LPS) or exogenous recombinant tumor necrosis factor-alpha (rTNF-alpha). As previously demonstrated for M phi, phagocytosis of zymosan particles during induction of enzyme activity enhanced subsequent NO2- production, which is of interest in light of the postulated phagocytic role of microglia within the CNS. Biochemical characterization of enzyme activity in intact microglial clones and in isolated cytosolic fractions indicates that the microglial NO synthase present in these murine cell clones represents the M phi-like isotype. These findings suggest that microglial cells could represent a major source of NO within the CNS.
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PMID:Inducible nitric oxide synthase activity of cloned murine microglial cells. 768 Oct 38

1. A murine macrophage cell line, J774, expressed nitric oxide (NO) synthase activity in response to interferon-gamma (IFN-gamma, 10 u ml-1) plus lipopolysaccharide (LPS, 10 ng ml-1). The enzyme activity was first detectable 6 h after incubation, peaked at 12 h and became undetectable after 48 h. 2. The decline in the NO synthase activity was not due to inhibition by stable substances secreted by the cells into the culture supernatant. 3. The decline in the NO synthase activity was significantly slowed down in cells cultured in a low L-arginine medium or with added haemoglobin, suggesting that NO may be involved in a feedback inhibitory mechanism. 4. The addition of NO generators, S-nitroso-acetyl-penicillamine (SNAP) or S-nitroso-glutathione (GSNO) markedly inhibited the NO synthase activity in a dose-dependent manner. The effect of NO on the enzyme was not due to the inhibition of de novo protein synthesis. 5. SNAP directly inhibited the inducible NO synthase extracted from activated J774 cells, as well as the constitutive NO synthase extracted from the rat brain. 6. The enzyme activity of J774 cells was not restored after the removal of SNAP by gel filtration, suggesting that NO inhibits NO synthase irreversibly.
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PMID:Feedback inhibition of nitric oxide synthase activity by nitric oxide. 768 40

Inflammatory cytokines (interleukin 1 alpha, 1 beta and tumor necrosis factor-alpha) induce the formation of nitrite by C6 astrocytoma cells in a manner that was blocked by inhibitors of NO synthase such as NG-monomethylarginine. They increase the formation of cGMP. This action was potentiated by isobutylmethylxanthine and was inhibited by NG-monomethylarginine. Interleukin-6 and interferon-gamma were inactive. It is concluded that the nitridergic signalling pathway is active in C6 cells and is a major target for inflammatory cytokines.
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PMID:IL1 and TNF alpha induce cGMP formation in C6 astrocytoma cells via the nitridergic pathway. 768 59

Murine macrophages express high levels of nitric oxide (NO) synthase and produce large amounts of NO when stimulated with interferon-gamma plus lipopolysaccharide in vitro. The expression of NO synthase peaks at 12 h after stimulation and declines rapidly to the background level by 72 h. These macrophages can be repeatedly reactivated to express similar levels of NO synthase. The reactivation is not due to newly divided cells since peritoneal macrophages which do not divide in vitro and J774 cells cultured in the presence of colchicine can also be restimulated to express NO synthase. The reactivation is accompanied by re-expression of NO synthase mRNA, as assessed by polymerase chain reaction analysis. Furthermore, the reactivated macrophages are fully capable of killing the intracellular protozoan parasite Leishmania major.
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PMID:Repeated induction of nitric oxide synthase and leishmanicidal activity in murine macrophages. 768 89

In primary rat cortical glial cell cultures lipopolysaccharide (LPS) induced a dose- and time-dependent increase of intracellular cyclic GMP concentration associated with a release of nitrite. The LPS-induced cyclic GMP and nitrite increase was enhanced by interferon-gamma and was prevented by L-NG-nitroarginine, dexamethasone and cycloheximide. Thus indicates that LPS effect occurred via the production of nitric oxide (NO) and involved new protein synthesis suggesting the induction of NO synthase in these cells. Furthermore this induction was Ca(2+)-independent and was blocked by an inhibitor of the synthesis of tetrahydrobiopterin. The inducible NO synthase was also expressed by C6 glioma cells. In primary mixed cultures containing both neuronal and glial cells, the effects of LPS were less important than in primary glial cell cultures suggesting that glial cells rather than neurons expressed the inducible form of NO synthase. On the other hand no change on neuronal viability was observed after NO synthase induction by LPS in this culture type. This study indicates that glial cells are able to induce NO synthase without affecting neuronal survival.
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PMID:Nitric oxide synthase induction in glial cells: effect on neuronal survival. 768 4

Murine macrophages produce nitric oxide (NO) from L-arginine on stimulation with lipopolysaccharide (LPS), alone or with interferon-gamma (IFN-gamma). The effect of incubation of macrophages with low concentrations of LPS on NO synthesis on subsequent stimulation was investigated, using a murine macrophage cell line, J774, and peritoneal macrophages from CBA mice. Cells which had been incubated with LPS produced significantly lower amounts of NO, and expressed lower levels of NO synthase activity, following stimulation with IFN-gamma and LPS, or with a high concentration of LPS. This effect was not reversed by tumor necrosis factor-alpha. The ability of CBA macrophages to kill the intracellular parasite Leishmania major was markedly reduced by pre-incubation with LPS. Reduced NO production by macrophages previously exposed to LPS is a manifestation of endotoxin tolerance, and may represent an important means of regulation of NO synthesis and thus a survival mechanism for intracellular parasites.
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PMID:Pre-exposure of murine macrophages to lipopolysaccharide inhibits the induction of nitric oxide synthase and reduces leishmanicidal activity. 768 61

Interleukin-10 (IL-10) has been reported to inhibit nitric oxide (NO) synthesis and microbicidal activity of interferon-gamma (IFN-gamma)-stimulated macrophages (M phi) by preventing the secretion of tumor necrosis factor-alpha (TNF-alpha) which serves as an autocrine activating signal. We have examined the effects of recombinant IL-10 on the capacity of IFN-gamma together with exogenous TNF-alpha to induce NO synthesis by bone marrow-derived M phi. Under these conditions and in contrast to its reported deactivating potential, IL-10 strongly enhanced NO synthesis measured as nitrite (NO2-) release (half maximal stimulation at approximately 10 U/ml). IL-10 further increased NO2- production by M phi stimulated in the presence of optimal concentrations of prostaglandin E2, a positive modulator of M phi activation by IFN-gamma/TNF-alpha. Increased steady state levels of NO synthase mRNA were observed in 4-h IFN-gamma/TNF-alpha cultures and enhanced NO2(-)-release was evident 24 h but not 48 h after stimulation. These results suggest that the effects of IL-10 on M phi function are more complex than previously recognized.
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PMID:Induction of macrophage nitric oxide production by interferon-gamma and tumor necrosis factor-alpha is enhanced by interleukin-10. 768 11

Taurine is present in high concentrations in most mammalian tissues, including those that prodigiously produce oxidants. Taurine protects against bronchiolar damage induced by NO2, ozone, bleomycin, and amiodarone. Taurine is chlorinated to form taurine chloramine (Tau-Cl) by the halide-dependent myeloperoxidase system and, under physiological conditions, reduces HOCl toxicity. Although NO and its metabolites, NO2- and NO3-, are thought to be major mediators of tissue damage resulting from oxidant exposure, cytokines, including tumor necrosis factor (TNF), are also involved. We examined the effects of Tau-Cl on NO production and TNF release by using RAW 264.7 cells activated with recombinant interferon-gamma (rIFN-gamma; 50 U/ml) and lipopolysaccharide (LPS; 10 micrograms/ml). NO was measured spectrophotometrically as NO2- after reaction with Griess reagent and TNF was measured by ELISA. Tau-Cl (0.5 mM) inhibits NO and TNF released into the medium by 47% and 43%, respectively. Tau-Cl is actively transported into RAW 264.7 cells by an uptake system that is energy, temperature, and Na+ dependent. Competition experiments demonstrate that the uptake system for Tau-Cl is distinct from that for taurine. In addition, the NO synthase activity of cytosolic preparations from activated RAW 264.7 cells is irreversibly inhibited by pretreatment with Tau-Cl. We demonstrate that Tau-Cl inhibits production of NO and TNF by activated macrophages and suggest a mechanism through which taurine supplementation may protect against oxidant-induced tissue damage.
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PMID:Taurine chloramine inhibits the synthesis of nitric oxide and the release of tumor necrosis factor in activated RAW 264.7 cells. 768 27

The murine macrophage cell line, J774, produced little or no detectable levels of nitric oxide (NO) when stimulated with interferon-gamma (IFN-gamma) alone in vitro. However, they expressed high levels of NO synthase and produced large amounts of NO when cultured with IFN-gamma in the presence of lipopolysaccharide (LPS). The synergistic action of LPS can be replaced by ingestion by the macrophages of zymosan, Staphylococcus aureus or Leishmania major in a dose-dependent manner. In contrast, the ingestion of particles such as latex beads or silica in the presence of IFN-gamma did not lead to the induction of NO synthase activity. Furthermore, ingestion of ink particles significantly reduced the ability of the macrophages to express NO synthase in response to the optimal stimulation of IFN-gamma and LPS. These results therefore demonstrate that phagocytosis per se is not sufficient to provide the additional signal for the induction of NO synthase activity in macrophages by IFN-gamma, and that the ingestion of certain particles can lead to the paralysis of the expression of this enzyme.
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PMID:Phagocytosis and induction of nitric oxide synthase in murine macrophages. 769 24

Recently, we have demonstrated that tumor necrosis factor (TNF)-sensitive tumor cells produce nitric oxide (NO) in response to TNF whereas TNF-resistant cells do not. Because the addition of interferon-gamma (IFN-gamma) augmented NO production, we were interested in investigating this phenomenon further and comparing the effects of IFN-gamma with those of IFN-alpha beta. We found that cell lines that are sensitive to TNF-mediated cytotoxicity (TMC) produced NO in response to TNF and IFN-gamma, but not in response to IFN-alpha beta. The effect of IFN-gamma on NO production was dose dependent, but IFN-gamma by itself did not induce NO production. A TNF-resistant cell line (MCA) did not produce NO under any of the conditions tested. Different results were obtained when the effect of IFNs on TMC was assayed. TNF-sensitive L929 cells were rendered less sensitive to TNF after treatment with both types of IFN. In contrast, another TNF-sensitive cell, WEHI 164, was rendered more sensitive to TMC after treatment with both types of IFN. The effect of IFNs on WEHI cells was dose dependent. Neither IFN had any effect on TNF sensitivity of TNF-resistant MCA cells. The addition of lipid A (LA) had no effect on TMC under any condition. However, L929 cells treated with LA, TNF, and IFN-gamma produced twice as much NO as cells treated with TNF and IFN-gamma only. Northern analysis for cytokine-inducible NO synthase (NOS) mRNA steady-state levels indicated that TNF synergized with IFN-gamma to induce increased accumulation of NOS mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interferon-gamma, but not interferon-alpha beta, synergizes with tumor necrosis factor-alpha and lipid A in the induction of nitric oxide production by murine L929 cells. 769 30


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