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First published on October 4, 2006; DOI: 10.1124/mol.106.028563

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Received for publication July 11, 2006.
Revised October 1, 2006.
Accepted for publication October 4, 2006.

Repression of human GSTA1 by interleukin-1{beta} is mediated by variant hepatic nuclear factor 1-C

Lorraine Ng 1, Kathleen Nichols 1, Kelly O'Rourke 1, Ann Maslen 1, Gordon Kirby 1*

1 University of Guelph

* Address correspondence to: E-mail: gkirby{at}uoguelph.ca

Abstract

Down-regulation of glutathione S-transferase alpha 1 (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 IL-1{beta} in Caco-2 cells. In luciferase reporter assays, overexpression of HNF-1{alpha} 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{alpha} rose concurrently in Caco-2 cells with increasing stage of confluency. IL-1{beta} reduced GSTA1 mRNA levels at all stages of confluency, however, HNF-1{alpha} mRNA levels were not altered. GSTA1 transcriptional activity was repressed by IL-1{beta}, an effect that was abolished by mutating the HRE. Similar results were observed in HT-29 cells and HepG2 cells. Overexpression of HNF-1{alpha} did not counteract IL-1{beta}-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 as vHNF-1C overexpression significantly reduced GSTA1 transcriptional activity. Finally, IL-1{beta} caused dose-related up-regulation of vHNF-1C mRNA levels and increased binding of vHNF-1C protein to the HRE whereas HNF-1{alpha}-HRE complex formation was reduced. These findings indicate that IL-1{beta} represses GSTA1 transcription via a mechanism involving overexpression of vHNF-1C.


Key words: Interleukins, Glutathione S-transferases, Regulation - transcriptional


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[Abstract] [Full Text] [PDF]


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