Intestinal Antiinflammatory Effect of 5-aminosalicylic Acid is Dependent on Peroxisome Proliferator-activated Receptor-gamma

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2005 Apr 13

PMID 15824083

Citations 195

Authors

Christel Rousseaux

Bruno Lefebvre

Laurent Dubuquoy

Philippe Lefebvre

Olivier Romano

Johan Auwerx

Daniel Metzger

Walter Wahli

Beatrice Desvergne

Gian Carlo Naccari

Philippe Chavatte

Amaury Farce

Philippe Bulois

Antoine Cortot

Jean Frederic Colombel

Pierre Desreumaux

Affiliations

Soon will be listed here.

Abstract

5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-gamma(+/-) mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-gamma expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element-driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-gamma as a target of 5-ASA underlying antiinflammatory effects in the colon.

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