The
peroxisome proliferator-activated receptor gamma (
PPARgamma) is highly expressed in the colon mucosa and its activation has been reported to protect against
colitis. We studied the involvement of
PPARgamma and its heterodimeric partner, the
retinoid X receptor (RXR) in intestinal inflammatory responses.
PPARgamma(1/)- and RXRalpha(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/
PPARgamma heterodimer in the protection against colon
inflammation was explored by the use of selective RXR and
PPARgamma agonists. TNBS-induced
colitis was significantly reduced by the administration of both
PPARgamma 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 1beta mRNA levels, a diminished
myeloperoxidase concentration, and reduction of
nuclear factor kappaB DNA binding activity, c-Jun NH(2)-terminal
kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of
PPARgamma and RXR
ligands was observed. In combination, these data demonstrate that activation of the RXR/
PPARgamma heterodimer protects against colon
inflammation and suggest that combination
therapy with both RXR and
PPARgamma ligands might hold promise in the clinic due to their synergistic effects.