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The Journal of Neuroscience, August 20, 2003, 23(20):7470-7478

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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

Je-Seong Won,^1,2 Yeong-Bin Im,¹ Lyndon Key,¹ Inderjit Singh,¹ and Avtar K. Singh^2,3

Departments of ¹Pediatrics and ²Pathology, Medical University of South Carolina, Charleston, South Carolina 29425, and ³Laboratory Medicine Service, Ralph Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29425

In rat glial cells the lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) gene expression was enhanced by extracellular glucose concentration in a dose-dependent manner. On the other hand, 2-deoxy-D-glucose decreased the LPS-induced iNOS gene expression even in the presence of glucose (6 gm/l), suggesting that glucose metabolism is linked to the regulation of iNOS gene expression. The intracellular NADPH/NADP⁺ directly correlated with the extracellular glucose concentration, and the reduction of NADPH generation via a block of glucose-6-phosphate dehydrogenase (G6PD) by treatment with dehydroepiandrosterone or the antisense DNA oligomer of G6PD mRNA resulted in the inhibition of iNOS gene expression. Gel shift assays showed that CAAT/enhancing binding protein (C/EBP), rather than AP-1 or NF-B, correlated better with a glucose-dependent increase in iNOS gene expression. The induction of C/EBP DNA binding activity by LPS and glucose was attributable mainly to the increase in C/EBP- protein. The cotransfection with wild-type C/EBP- increased the iNOS promoter activity to the level achieved with a higher glucose concentration in the presence of LPS. Therefore, our results suggest that C/EBP- may be a critical mediator in glucose-mediated regulation of iNOS gene expression.

Key words: C/EBP; astrocytes; glucose; G6PD; iNOS; NADPH; NF-B; nitric oxide

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Received Aug. 12, 2002; revised May. 27, 2003; accepted Jun. 5, 2003.

This article has been cited by other articles:

				R. Matsui, S. Xu, K. A. Maitland, R. Mastroianni, J. A. Leopold, D. E. Handy, J. Loscalzo, and R. A. Cohen Glucose-6-Phosphate Dehydrogenase Deficiency Decreases Vascular Superoxide and Atherosclerotic Lesions in Apolipoprotein E-/- Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 910 - 916. [Abstract] [Full Text] [PDF]

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