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Down‐regulation of GSTA1 by IL‐1 beta is mediated by overexpression of the transdominant repressor vHNF‐1C
Author(s) -
Kirby Gordon M,
Ng Lorraine
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a261-c
Subject(s) - repressor , microbiology and biotechnology , activator (genetics) , messenger rna , reporter gene , transcription (linguistics) , promoter , luciferase , gene isoform , psychological repression , biology , transcription factor , chemistry , beta (programming language) , gene expression , transfection , gene , biochemistry , linguistics , philosophy , computer science , programming language
Interleukin‐1 (IL‐1) beta markedly suppresses glutathione S‐transferase (GST) A1 expression, which has profound implications on protection against cytotoxic byproducts of inflammation. We investigated the role of hepatic nuclear factor 1 (HNF‐1) alpha in the regulation of human GSTA1 by IL‐1 beta in Caco‐2 cells. Overexpression of HNF‐1 alpha increased GSTA1 promoter activity in luciferase reporter assays through a HNF‐1 response element (HRE) in the proximal promoter. IL‐1 beta repressed GSTA1 transcriptional activity in reporter assays but not when the HRE was mutated in luciferase contsructs. Both GST and HNF‐1 alpha mRNA and protein levels progressively increased as cells reached 7 days post‐confluency, however, only GSTA1 mRNA levels were reduced by IL‐1 beta. Overexpression of HNF‐1 alpha failed to counteract IL‐1 beta‐mediated repression of GSTA1 transcription both in reporter assays and at the mRNA level. Moreover, IL‐1 beta had no effect on HNF‐1 alpha binding to the HRE in gel shift assays. Messenger RNA levels of the C isoform of variant HNF‐1 (vHNF‐1C), the transdominant repressor variant form, were 60 fold higher relative to the A and B forms (transcriptional activator forms) in pre‐confluent cells but only 20 fold higher in confluent cells. IL‐1 beta significantly up‐regulated vHNF‐1C expression in pre‐confluent and confluent cells to 80 fold and 30 fold respectively. These findings indicate that IL‐1 beta represses GSTA1 transcription via a mechanism involving overexpression of vHNF‐1C. Supported by the Canadian Institutes for Health Research