PPARβ/δ protects against experimental colitis through a ligand-independent mechanism

Peroxisome proliferator-activated receptors (PPARs) beta/delta and gamma have overlapping roles in the negative regulation of inflammatory response genes. Ligand activation of PPAR gamma protects against experimental colitis in mice. PPAR beta/delta can negatively regulate inflammation and is highly expressed in the epithelial cells of the colon, therefore PPAR beta/delta may also have a role in experimental colitis. In these studies, colitis was induced by dextran sodium sulfate (DSS) treatment in wild-type and PPAR beta/delta-null mice, with and without the PPAR beta/delta specific ligand GW0742. PPAR beta/delta-null mice exhibited increased sensitivity to DSS-induced colitis, as shown by marked differences in body weight loss, colon length, colonic morphology, myeloperoxidase activity and increased expression of mRNAs encoding the inflammatory markers interferon gamma, tumor necrosis factor-alpha, and interleukin-6 compared to similarly treated wild-type mice. Interestingly, these differences were not affected by ligand activation of PPAR beta/delta in either genotype. These studies demonstrate that PPAR beta/delta expression in the colonic epithelium inhibits inflammation and protects against DSS-induced colitis through a ligand-independent mechanism.