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Repression of Human GSTA1 by Interleukin-1 Is Mediated by Variant Hepatic Nuclear Factor-1C

Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada

Down-regulation of glutathione transferase A1 (GSTA1) expression has profound implications in cytoprotection against toxic by-products of lipid peroxidation produced during inflammation. We investigated the role of hepatic nuclear factor 1 (HNF-1) in repression of human GSTA1 expression by interleukin (IL)-1 in Caco-2 cells. In luciferase reporter assays, overexpression of HNF-1 increased GSTA1 transcriptional activity via an HNF-1 response element (HRE) in the proximal promoter. In addition, constitutive mRNA levels of GSTA1 and HNF-1 rose concurrently in Caco-2 cells with increasing stage of confluence. IL-1 reduced GSTA1 mRNA levels at all stages of confluence; however, HNF-1 mRNA levels were not altered. IL-1 repressed GSTA1 transcriptional activity, an effect that was abolished by mutating the HRE. Similar results were observed in HT-29 and HepG2 cells. Overexpression of HNF-1 did not counteract IL-1-mediated repression of GSTA1 transcription either in reporter assays or at the mRNA level. Involvement of the transdominant repressor C isoform of variant HNF-1 (vHNF-1C) in GSTA1 repression was demonstrated, because vHNF-1C overexpression significantly reduced GSTA1 transcriptional activity. Finally, IL-1 caused concentration-related up-regulation of vHNF-1C mRNA levels and increased binding of vHNF-1C protein to the HRE, whereas HNF-1-HRE complex formation was reduced. These findings indicate that IL-1 represses GSTA1 transcription via a mechanism involving overexpression of vHNF-1C.

Address correspondence to: Dr. Gordon M. Kirby, Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1. E-mail: gkirby{at}uoguelph.ca

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				R. I. Dmitrieva, C. A. Hinojos, E. Boerwinkle, M. C. Braun, M. Fornage, and P. A. Doris Hepatocyte Nuclear Factor 1 and Hypertensive Nephropathy Hypertension, June 1, 2008; 51(6): 1583 - 1589. [Abstract] [Full Text] [PDF]