5-ASA MoA ON PPAR
5-aminosalicylic acid (5-ASA) or mesalamine is an anti-inflammatory 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.
Testing the possibility
To test this possibility, colitis was induced in heterozygous PPAR gamma (+/-) mice and their wild-type litter-mates, 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 co-activators 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 anti-inflammatory effects in the colon (Rousseaux C, Desreumaux P et al, J Exp Med. 2005 Apr 18; 201(8):1205-15).