Peroxisome proliferator activated receptor γ in colonic epithelial cells protects against experimental inflammatory bowel disease

Introduction: Peroxisome proliferator activated receptor gamma (PPAR gamma) is expressed in epithelial cells, macrophage, and T and B lymphocytes. Ligand induced activation of PPAR gamma was reported to attenuate colitis activity but it is not clear whether this protection is mediated by epithelial or leucocyte PPAR gamma. Methods: Mice with targeted disruption of the PPAR gamma gene in intestinal epithelial cells, generated using a villin-Cre transgene and floxed PPAR gamma allele and designated PPAR gamma(Delta IEpC), were compared with littermate mice having only the PPAR gamma floxed allele with no Cre transgene that expressed PPAR gamma in the gut, designated PPAR gamma(F/F). Colitis was induced by administering dextran sodium sulphate (DSS) and the two mouse lines compared for typical symptoms of disease and expression of inflammatory cytokines. \ Results: PPAR gamma(Delta IEpC) mice displayed reduced expression of the PPAR gamma target genes ADRP and FABP in the gut but were otherwise normal. Increased susceptibility to DSS induced colitis, as defined by body weight loss, colon length, diarrhoea, bleeding score, and altered histology, was found in PPAR gamma(Delta DIEpC) mice in comparison with PPAR gamma(F/F) mice. Interleukin (IL)-6, IL-1 beta, and tumour necrosis factor a mRNA levels in colons of PPAR gamma Delta(DIEpC) mice treated with DSS were higher than in similarly treated PPAR gamma(F/F) mice. The PPAR gamma ligand rosiglitazone decreased the severity of DSS induced colitis and suppressed cytokine production in both PPAR gamma(F/F) and PPAR gamma Delta(DIEpC) mice. Conclusions: These studies reveal that PPAR gamma expressed in the colonic epithelium has an endogenous role in protection against DSS induced colitis and that rosiglitazone may act through a PPARc independent pathway to suppress inflammation.