The Journal of Experimental Medicine
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Published online 11 April 2005 doi:10.1084/jem.20041948
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 8, 1205-1215
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ARTICLE

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

Christel Rousseaux1, Bruno Lefebvre2, Laurent Dubuquoy3, Philippe Lefebvre2, Olivier Romano1, Johan Auwerx3, Daniel Metzger3, Walter Wahli4, Béatrice Desvergne4, Gian Carlo Naccari5, Philippe Chavatte6, Amaury Farce6, Philippe Bulois1, Antoine Cortot1, Jean Frédéric Colombel1, and Pierre Desreumaux1

1 Institut National de la Santé et de la Recherche Medicale (INSERM) 0114, Physiopathologie des Maladies Inflammatoires Intestinales, CHU 59037 Lille, France
2 INSERM U459, Faculté de Médecine, 59045 Lille Cedex, France
3 Institut de Génétique et Biologie Moléculaire et Cellulaire, INSERM, Centre National de la Recherche Scientifique, Université Louis Pasteur, 67404 Illkirch, France
4 Centre Intégratif de Génomique, Pôle de Recherche National, Aux Frontières de la Génétique, Université de Lausanne, Lausanne CH1015, Switzerland
5 Giuliani SpA, 20129 Milano, Italy
6 Laboratoire de Chimie Thérapeutique, EA1043, Faculté des Sciences Pharmaceutiques et Biologiques, 59006 Lille Cedex, France

CORRESPONDENCE Pierre Desreumaux: pdesreumaux{at}chru-lille.fr

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.

Abbreviations used: 5-ASA, 5-aminosalicylic acid; DRIP, vitamin D3 receptor–interacting protein; GST, glutathione S-transferase; IBD, inflammatory bowel disease; IC50, concentration resulting in 50% inhibition; LBD, ligand-binding domain; MPO, methyl peroxidase; PPAR, peroxisome proliferator–activated receptor; PPRE, peroxisome-proliferator response element; RXR, retinoid x receptor; TNBS, trinitrobenzene sulfonic acid.

C. Rousseaux and B. Lefebvre contributed equally to this work.


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