Impaired expression of peroxisome proliferator-activated receptor γ in ulcerative colitis

Background & Aims: The peroxisome proliferator-activated receptor gamma (PPARgamma) has been proposed as a key inhibitor of colitis through attenuation of nuclear factor kappaB (NF-kappaB) activity. In inflammatory bowel disease, activators of NF-kappaB, including the bacterial receptor to like receptor (TLR)4, are elevated. We aimed to determine the role of bacteria and their signaling effects on PPARgamma regulation during inflammatory bowel disease (IBD). Methods: TLR4-transfected Caco-2 cells, germfree mice, and mice devoid of functional TLR4 (Lps(d)/ Lps(d) mice) were assessed for their expression of PPARgamma in colonic tissues in the presence or absence of bacteria. This nuclear receptor expression and the polymorphisms of gene also were assessed in patients with Crohn's disease (CD) and ulcerative colitis (UC), 2 inflammatory bowel diseases resulting from an abnormal immune response to bacterial antigens. Results: TLR4-transfected Caco-2 cells showed that the TLR4 signaling pathway elevated PPARgamma expression and a PPARgamma-dependent reporter in an Ikappakappabeta dependent fashion. Murine and human intestinal flora induced PPARgamma expression in colonic: epithelial cells of control mice. PPARgamma expression was significantly higher in the colon of control compared with Lps(d)/Lps(d) mice. Although PPARgamma levels appeared normal in patients with CD and controls, UC patients displayed a reduced expression of PPARgamma confined to colonic epithelial cells, without any mutation in the PPARgamma gene. Conclusions: These data showed that the commensal intestinal flora affects the expression of PPARgamma and that PPARgamma expression is considerably impaired in patients with UC.