Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor γ (BPARγ) heterodimer:: A basis for new therapeutic strategies

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPAR gamma and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPAR gamma (+/-) and RXR alpha (+/-) 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 gamma heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPAR gamma agonists. TNBS-induced colitis was significantly reduced by the administration of both PPAR gamma 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 alpha and interleukin 1 beta mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor kappaB DNA binding activity, c-Jun NH2-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPAR gamma and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPAR gamma heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPAR gamma ligands might hold promise in the clinic due to their synergistic effects.