Inducible nitric oxide synthase expression is selectively induced in astrocytes isolated from adult human brain

Zhao, Meng; Liu, Judy S. H.; He, Deke; Dickson, Dennis W.; Lee, Sunhee C.

doi:10.1016/s0006-8993(98)01023-3

Cited by 68 publications

(34 citation statements)

References 20 publications

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“…Although lipopolysaccharide is a potent inducer of iNOS in microglia, it has not been demonstrated to have a physiological relevance in MS (39). IFN-␥, alone or in combinations with other proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣) and IL-1␤, can also induce iNOS in microglia (7,24,25,28); however, microglia isolated from adult human brain tend to be a poor source of iNOS-derived NO in response to these proinflammatory cytokines (40,41). These observations suggest that apart from proinflammatory cytokines, microglia can be activated by some other mechanism(s) for the induction of iNOS in the CNS of MS patients.…”

Section: Discussionmentioning

confidence: 99%

Myelin Basic Protein-primed T Cells Induce Nitric Oxide Synthase in Microglial Cells

Dasgupta

Jana

Liu

et al. 2002

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Myelin Basic Protein-primed T Cells Induce Nitric Oxide Synthase in Microglial Cells

Dasgupta

Jana

Liu

et al. 2002

Journal of Biological Chemistry

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“…Astrocytes-Human primary astrocytes have been shown to induce the expression of iNOS in the presence of different proinflammatory cytokines (22)(23)(24). Since gemfibrozil potently inhibited the expression of iNOS in human U373MG astroglial cells, we examined the effect of gemfibrozil on cytokine-induced expression of iNOS in human primary astrocytes.…”

Section: Inhibition Of Cytokine-induced Production Of No By Gemfibrozmentioning

confidence: 99%

Gemfibrozil, a Lipid-lowering Drug, Inhibits the Induction of Nitric-oxide Synthase in Human Astrocytes

Pahan

Jana

Liu

et al. 2002

Journal of Biological Chemistry

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Gemfibrozil, a lipid-lowering drug, inhibited cytokine-induced production of NO and the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astrocytes. Similar to gemfibrozil, clofibrate, another fibrate drug, also inhibited the expression of iNOS. Inhibition of human iNOS promoter-driven luciferase activity by gemfibrozil in cytokine-stimulated U373MG astroglial cells suggests that this compound inhibits the transcription of iNOS. Since gemfibrozil is known to activate peroxisome proliferator-activated receptor-␣ (PPAR-␣), we investigated the role of PPAR-␣ in gemfibrozil-mediated inhibition of iNOS. Gemfibrozil induced peroxisome proliferator-responsive element (PPRE)-dependent luciferase activity, which was inhibited by the expression of ⌬hPPAR-␣, the dominant-negative mutant of human PPAR-␣. However, ⌬hPPAR-␣ was unable to abrogate gemfibrozil-mediated inhibition of iNOS suggesting that gemfibrozil inhibits iNOS independent of PPAR-␣. The human iNOS promoter contains consensus sequences for the binding of transcription factors, including interferon-␥ (IFN-␥) regulatory factor-1 (IRF-1) binding to interferon-stimulated responsive element (ISRE), signal transducer and activator of transcription (STAT) binding to ␥-activation site (GAS), nuclear factor-B (NF-B), activator protein-1 (AP-1), and CCAAT/enhancer-binding protein ␤ (C/EBP␤); therefore, we investigated the effect of gemfibrozil on the activation of these transcription factors. The combination of interleukin (IL)-1␤ and IFN-␥ induced the activation of NF-B, AP-1, C/EBP␤, and GAS but not that of ISRE, suggesting that IRF-1 may not be involved in cytokine-induced expression of iNOS in human astrocytes. Interestingly, gemfibrozil strongly inhibited the activation of NF-B, AP-1, and C/EBP␤ but not that of GAS in cytokine-stimulated astroglial cells. These results suggest that gemfibrozil inhibits the induction of iNOS probably by inhibiting the activation of NF-B, AP-1, and C/EBP␤ and that gemfibrozil, a prescribed drug for humans, may further find its therapeutic use in neuroinflammatory diseases.

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“…It has been shown that the levels of IL-1␤ (Cacabelos et al, 1994), IL-6 (Hüll et al, 1996), and TNF-␣ (Perry et al, 2001) are upregulated in AD brains. Moreover, NO, catalyzed by iNOS, may also be involved in the pathological processes of AD (Lüth et al, 2002), although the presence of iNOS in human microglia is disputed (Colasanti et al, 1995;Zhao et al, 1998;Heneka et al, 2001). The neurotoxic effects of NO are, in general, attributed to its reaction with O 2 Ϫ to form peroxynitrite, which can cause oxidative damage to proteins and other macromolecules, all of which are seen in the brain of AD patients (Koppal et al, 1999;Torreilles et al, 1999).…”

mentioning

confidence: 99%

Thrombin-Induced Oxidative Stress Contributes to the Death of Hippocampal NeuronsIn Vivo: Role of Microglial NADPH Oxidase

Choi¹,

Lee²,

Kim³

et al. 2005

J. Neurosci.

146

138

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The present study investigated whether thrombin, a potent microglial activator, can induce reactive oxygen species (ROS) generation through activation of microglial NADPH oxidase and if this may contribute to oxidative damage and consequent neurodegeneration. Seven days after intrahippocampal injection of thrombin, Nissl staining and immunohistochemistry using the neuronal-specific nuclear protein NeuN revealed a significant loss in hippocampal CA1 neurons. In parallel, thrombin-activated microglia, assessed by OX-42 and OX-6 immunohistochemistry, and ROS production, assessed by hydroethidine histochemistry, were observed in the hippocampal CA1 area in which degeneration of hippocampal neurons occurred.

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Inducible nitric oxide synthase expression is selectively induced in astrocytes isolated from adult human brain

Cited by 68 publications

References 20 publications

Myelin Basic Protein-primed T Cells Induce Nitric Oxide Synthase in Microglial Cells

Myelin Basic Protein-primed T Cells Induce Nitric Oxide Synthase in Microglial Cells

Gemfibrozil, a Lipid-lowering Drug, Inhibits the Induction of Nitric-oxide Synthase in Human Astrocytes

Thrombin-Induced Oxidative Stress Contributes to the Death of Hippocampal NeuronsIn Vivo: Role of Microglial NADPH Oxidase

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