Th1 cytokine-induced downregulation of PPARγ in human biliary cells relates to cholangitis in primary biliary cirrhosis

Peroxisome proliferator-activated receptor-γ (PPARγ) is known to inhibit the production of proinflammatory cytokines. In Th1-predominant diseases, PPARγ ligands can ameliorate clinical severity by downregulating the expression of proinflammatory cytokines. Primary biliary cirrhosis (PBC) is characterized by chronic destructive cholangitis with a Th1-predominant cytokine milieu. Unusual immune responses to infectious agents are suspected to underlie its etiopathogenesis. We examined the significance of PPARγ in biliary inflammation in connection to PBC. To this end, we performed immunohistochemistry, quantitative polymerase chain reaction, and nuclear factor-kappaB (NF-κB) DNA-binding assays to clarify the intrahepatic distribution of PPARγ and the regulation of PPARγ by inflammatory cytokines and PPARγ ligand in five cultured biliary cell lines including one derived from PBC liver. In liver specimens from patients with PBC, PPARγ protein was ubiquitously expressed in intrahepatic biliary epithelium, whereas the expression of PPARγ protein and mRNA was reduced in damaged bile ducts. PPARγ expression in cultured cells was upregulated by interleukin-4 (IL-4; Th2-type), but downregulated by IFN-γ (Th1-type). PPARγ ligand negatively modulated lipopolysaccharide-induced NF-κB activation. Moreover, this inhibitory effect of PPARγ ligand was attenuated by pretreatment with IFN-γ. In conclusion, PPARγ may be important to maintain homeostasis in the intrahepatic biliary epithelium, and its reduction in the bile ducts of PBC liver may be associated with the Th1-predominant milieu and with the development of chronic cholangitis in PBC. Immunosuppression using PPARγ ligands may be of therapeutic benefit to attenuate biliary inflammation in PBC.