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Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator–activated receptor-γ

2005; Rockefeller University Press; Volume: 201; Issue: 8 Linguagem: Inglês

10.1084/jem.20041948

1540-9538

Christel Rousseaux, Bruno Lefebvre, Laurent Dubuquoy, Philippe Lefèbvre, Olivier Romano, Johan Auwerx, Daniel Metzger, Walter Wahli, Béatrice Desvergne, G.C. Naccari, Philippe Chavatte, Amaury Farce, P. Bulois, Antoine Cortot, Jean Frédéric Colombel, Pierre Desreumaux,

Eicosanoids and Hypertension Pharmacology

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-γ (PPAR-γ) 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-γ+/− 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-γ 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-γ as a target of 5-ASA underlying antiinflammatory effects in the colon.