RT Journal Article SR Electronic T1 Down-Regulation of Alpha Class GlutathioneS-Transferase by Interleukin-1β in Human Intestinal Epithelial Cells (Caco-2) in Culture JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1186 OP 1193 DO 10.1124/dmd.30.11.1186 VO 30 IS 11 A1 Laura Romero A1 Marnie A. Higgins A1 James Gilmore A1 Kim Boudreau A1 Ann Maslen A1 Heather J. Barker A1 Gordon M. Kirby YR 2002 UL http://dmd.aspetjournals.org/content/30/11/1186.abstract AB The influence of pro-inflammatory cytokines on alpha class glutathione S-transferase A1 and A2 (GSTA1/A2) expression was examined in human colonic epithelial cells (Caco-2) in culture. Dose-dependent reductions in GSTA1/A2 mRNA, protein, and activity levels occurred in Caco-2 cells cultured in conditioned medium (CM) from lipopolysaccharide-stimulated murine monocyte-macrophage cells (RAW 264.7). Neutralizing anti-interleukin-1β (IL-1β) antibodies attenuated this repression of GSTA1/A2 expression by CM. Moreover, recombinant human IL-1β reduced GSTα expression at the mRNA, protein, and activity levels in a dose-related fashion. Reduction of GSTA1/A2 mRNA levels by IL-1β was attenuated by pretreatment with IL-1 receptor antagonist. GSTA1/A2 mRNA half-lives were similar in control and IL-1β-treated cells, indicating that IL-1β has no effect on mRNA stability. In reporter gene studies, IL-1β caused a dose-related reduction of luciferase activity in Caco-2 cells transfected with the full-length GSTA1 promoter-luciferase construct. Using truncated constructs, IL-1β responsiveness was mapped to a region 286 base pairs upstream to the coding region. Deletion of a hepatic nuclear factor 1 (HNF-1) site in this region abrogated the IL-1β-mediated repression of GSTA1 promoter activity. These results demonstrate that IL-1β down-regulates GSTA1/A2 expression in cultured human enterocytes by a transcriptional mechanism involving an HNF-1 site. The American Society for Pharmacology and Experimental Therapeutics