The Involvement of Glucose Metabolism in the Regulation of Inducible Nitric Oxide Synthase Gene Expression in Glial Cells: Possible Role of Glucose-6-Phosphate Dehydrogenase and CCAAT/Enhancing Binding Protein

Won, Je-Seong; Im, Yeong‐Bin; Key, L. Lyndon; Singh, Inderjit; Singh, Avtar

doi:10.1523/jneurosci.23-20-07470.2003

Cited by 40 publications

(36 citation statements)

References 42 publications

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“…The direct effect of glucose availability on inflammatory response at the cellular level has been described. LPS-induced NO/iNOS induction was increased at high glucose-cultured cells than normal glucose-cultured cells via enhancing activation of NF-B (30,38,39). We newly propose in this report that glucose availability sensed by HBP flux influences the regulation of inflammation.…”

Section: Discussionmentioning

confidence: 53%

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Lipopolysaccharide (LPS)-stimulated iNOS Induction Is Increased by Glucosamine under Normal Glucose Conditions but Is Inhibited by Glucosamine under High Glucose Conditions in Macrophage Cells

Hwang

Kwon

Kim

et al. 2017

Journal of Biological Chemistry

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Edited by Dennis R. VoelkerWe investigated the regulatory effect of glucosamine (GlcN) for the production of nitric oxide (NO) and expression of inducible NO synthase (iNOS) under various glucose conditions in macrophage cells. At normal glucose concentrations, GlcN dose dependently increased LPS-stimulated production of NO/iNOS. However, GlcN suppressed NO/iNOS production under high glucose culture conditions. Moreover, GlcN suppressed LPS-induced up-regulation of COX-2, IL-6, and TNF-␣ mRNAs under 25 mM glucose conditions yet did not inhibit upregulation under 5 mM glucose conditions. Glucose itself dose dependently increased LPS-induced iNOS expression. LPS-induced MAPK and IB-␣ phosphorylation did not significantly differ at normal and high glucose conditions. The activity of LPS-induced nuclear factor-B (NF-B) and DNA binding of c-Rel to the iNOS promoter were inhibited under high glucose conditions in comparison with no significant changes under normal glucose conditions. In addition, we found that the LPS-induced increase in O-GlcNAcylation as well as DNA binding of c-Rel to the iNOS promoter were further increased by GlcN under normal glucose conditions. However, both O-GlcNAcylation and DNA binding of c-Rel decreased under high glucose conditions. The NF-B inhibitor, pyrrolidine dithiocarbamate, inhibited LPS-induced iNOS expression under high glucose conditions but it did not influence iNOS induction under normal glucose conditions. In addition, pyrrolidine dithiocarbamate inhibited NF-B DNA binding and c-Rel O-GlcNAcylation only under high glucose conditions. By blocking transcription with actinomycin D, we found that stability of LPS-induced iNOS mRNA was increased by GlcN under normal glucose conditions. These results suggest that GlcN regulates inflammation by sensing energy states of normal and fuel excess.

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Section: Discussionmentioning

confidence: 53%

“…Among these transcriptional factors, C/EBP-␦ may be a critical mediator in glucose-mediated regulation of iNOS gene expression in response to LPS (39). We found that C/EBP-␦ protein expression was reduced as the glucose concentration increased with or without LPS.…”

Section: Discussionmentioning

confidence: 73%

Lipopolysaccharide (LPS)-stimulated iNOS Induction Is Increased by Glucosamine under Normal Glucose Conditions but Is Inhibited by Glucosamine under High Glucose Conditions in Macrophage Cells

Hwang

Kwon

Kim

et al. 2017

Journal of Biological Chemistry

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“…Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays as described previously (50). BV2 microglia proliferation was measured by BrdU incorporation assay.…”

Section: Cell Viability and Proliferation Assaymentioning

confidence: 99%

STAT3 Regulation by S-Nitrosylation: Implication for Inflammatory Disease

Kim

Won²,

Singh³

et al. 2014

Antioxidants & Redox Signaling

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Aims: S-nitrosylation and S-glutathionylation, redox-based modifications of protein thiols, are recently emerging as important signaling mechanisms. In this study, we assessed S-nitrosylation-based regulation of Janus-activated kinase 2/signal transducer and activator of transcription 3 ( JAK2/STAT3) pathway that plays critical roles in immune/inflammatory responses and tumorigenesis. Results: Our studies show that STAT3 in stimulated microglia underwent two distinct redox-dependent modifications, S-nitrosylation and S-glutathionylation. STAT3 S-nitrosylation was associated with inducible nitric oxide synthase (iNOS)-produced nitric oxide (NO) and S-nitrosoglutathione (GSNO), whereas S-glutathionylation of STAT3 was associated with cellular oxidative stress. NO produced by iNOS or treatment of microglia with exogenous GSNO inhibited STAT3 activation via inhibiting STAT3 phosphorylation (Tyr 705 ). Consequently, the interleukin-6 (IL-6)-induced microglial proliferation and associated gene expressions were also reduced. In cell-free kinase assay using purified JAK2 and STAT3, STAT3 phosphorylation was inhibited by its selective preincubation with GSNO, but not by preincubation of JAK2 with GSNO, indicating that GSNO-mediated mechanisms inhibit STAT3 phosphorylation through S-nitrosylation of STAT3 rather than JAK2. In this study, we identified that

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“…Although most of the studies related to manipulation of iNOS promoter have been performed in non-CNS cells, a few studies have also registered the activation of iNOS promoter in mouse and rat glial cells (13,106,117,143). In recent past, our lab has mainly concentrated on the activation of human iNOS promoter in human U373MG astroglial cells and primary astrocytes.…”

Section: Transcriptional Regulationmentioning

confidence: 99%

Regulation of Inducible Nitric Oxide Synthase Gene in Glial Cells

Saha

Pahan

2006

Antioxidants & Redox Signaling

311

262

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Elevated levels of NO produced within the central nervous system (CNS) are associated with the pathogenesis of neuroinflammatory and neurodegenerative human diseases such as multiple sclerosis, HIV dementia, brain ischemia, trauma, Parkinson's disease, and Alzheimer's disease. Resident glial cells in the CNS (astroglia and microglia) express inducible nitric oxide synthase (iNOS) and produce high levels of NO in response to a wide variety of proinflammatory and degenerative stimuli. Although pathways resulting in the expression of iNOS may vary in two different glial cells of different species, the intracellular signaling events required for the expression of iNOS in these cells are slowly becoming clear. Various signaling cascades converge to activate several transcription factors that control the transcription of iNOS in glial cells. The present review summarizes different results and discusses current understandings about signaling mechanisms for the induction of iNOS expression in activated glial cells. A complete understanding of the regulation of iNOS expression in glial cells is expected to identify novel targets for therapeutic intervention in NO-mediated neurological disorders.

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The Involvement of Glucose Metabolism in the Regulation of Inducible Nitric Oxide Synthase Gene Expression in Glial Cells: Possible Role of Glucose-6-Phosphate Dehydrogenase and CCAAT/Enhancing Binding Protein

Abstract: In rat glial cells the lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS

Cited by 40 publications

References 42 publications

Lipopolysaccharide (LPS)-stimulated iNOS Induction Is Increased by Glucosamine under Normal Glucose Conditions but Is Inhibited by Glucosamine under High Glucose Conditions in Macrophage Cells

Lipopolysaccharide (LPS)-stimulated iNOS Induction Is Increased by Glucosamine under Normal Glucose Conditions but Is Inhibited by Glucosamine under High Glucose Conditions in Macrophage Cells

STAT3 Regulation by S-Nitrosylation: Implication for Inflammatory Disease

Regulation of Inducible Nitric Oxide Synthase Gene in Glial Cells

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