TY - JOUR T1 - Down-Regulation of Alpha Class Glutathione<em>S</em>-Transferase by Interleukin-1β in Human Intestinal Epithelial Cells (Caco-2) in Culture JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1186 LP - 1193 DO - 10.1124/dmd.30.11.1186 VL - 30 IS - 11 AU - Laura Romero AU - Marnie A. Higgins AU - James Gilmore AU - Kim Boudreau AU - Ann Maslen AU - Heather J. Barker AU - Gordon M. Kirby Y1 - 2002/11/01 UR - http://dmd.aspetjournals.org/content/30/11/1186.abstract N2 - 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 ER -