Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPAR?)-deficient mice

Background Peroxisome proliferator activated receptor alpha (PPAR?) , a regulator of enzymes involved in ß oxidation , has been reported to influence lymphocyte activation. The purpose of this study was to determine whether PPAR? plays a role in T cell-mediated hepatitis induced by Concanavalin A (ConA). Methods Wild type (wt) or PPAR?-deficient (PPAR?) mice were treated with ConA (15 mg/kg) by intravenous injection 0 , 10 or 24 h prior to sacrifice and serum and tissue collection for analysis of tissue injury , cytokine response , T cell activation and characterization. Results Ten and 24 h following ConA administration , wt mice had significant liver injury as demonstrated by serum transaminase levels , inflammatory cell infiltrate , hepatocyte apoptosis , and expression of several cytokines including interleukin 4 (IL4) and interferon gamma (IFNy). In contrast , PPAR? mice were protected from ConA-induced liver injury with significant reductions in serum enzyme release , greatly reduced inflammatory cell infiltrate , hepatocellular apoptosis , and IFNy expression , despite having similar levels of hepatic T cell activation and IL4 expression. This resistance to liver injury was correlated with reduced numbers of hepatic natural killer T (NKT) cells and their in vivo responsiveness to alpha-galactosylceramide. Interestingly , adoptive transfer of either wt or PPAR?ˆ’/ˆ’ splenocytes reconstituted ConA liver injury and cytokine production in lymphocyte-deficient , severe combined immunodeficient mice implicating PPAR? within the liver , possibly through support of IL15 expression and/or suppression of IL12 production and not the lymphocyte as the key regulator of T cell activity and ConA-induced liver injury. Conclusion Taken together , these data suggest that PPAR? within the liver plays an important role in ConA-mediated liver injury through regulation of NKT cell recruitment and/or survival