Original Article

Attenuation of Colon Inflammation through Activators of the Retinoid X Receptor (RXR)/Peroxisome Proliferator–activated Receptor (PPAR) Heterodimer: A Basis for New Therapeutic Strategies

Correspondence to: Pierre Desreumaux, Service de Gastroentérologie, Hôpital Huriez, CHU Lille 59037, France. Tel:33-3-20-44-47-14 Fax:33-3-20-44-47-13 E-mail:pdesreumaux{at}chru-lille.fr.

The peroxisome proliferator–activated receptor (PPAR) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPAR and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPAR^1/- and RXR^1/- mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPAR heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPAR agonists. TNBS-induced colitis was significantly reduced by the administration of both PPAR and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor and interleukin 1ß mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor B DNA binding activity, c-Jun NH₂-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPAR and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPAR heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPAR ligands might hold promise in the clinic due to their synergistic effects.

Key Words: colitis, inflammatory bowel disease, nuclear receptors, tumor necrosis factor , signal transduction pathway

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