Deletion of Interleukin-12p40 Suppresses Autoimmune Cholangitis in Dominant Negative Transforming Growth Factor β Receptor Type II Mice

Our laboratory has reported that mice that express a dominant negative form of transforming growth factor beta receptor restricted to T cells (dnTGF beta RII) develop an inflammatory biliary ductular disease with elevated serum levels of interleukin (IL)-12p40 and other proinflammatory cytokines and antimitochondrial autoantibodies (AMAs) closely resembling human primary biliary cirrhosis (PBC). We have used this mouse model to address the potential mechanisms of immunomodulation of liver disease by creating two unique genetic strains: IL-12p40 knockout (KO)-dnTGF beta RII mice and IFN-gamma KO-dnTGF beta RII mice. The two colonies of genetically modified mice-and, for purposes of controls, the dnTGF beta RII mice-were monitored for liver immunopathology, AMAs, and intrahepatic cytokine production. Disease expression in the IFN-gamma KO-dnTGF beta RII mice, including liver immunopathology, were similar to those of dnTGF beta RII mice, whereas the IL-12p40 KO-dnTGF beta RII mice had a dramatic reduction in histological autoimmune cholangitis and significant decreases in levels of intrahepatic proinflammatory cytokines, but similar levels of AMAs compared with dnTGF beta RII controls. Conclusion: These data indicate that in this mouse model of PBC, signaling by way of IL-12p40 is an essential requirement for the development of autoimmune cholangitis. The results of these studies will play an important role in identifying pathways and reagents that will selectively inhibit IL-12 signaling for the outlining of future therapeutic strategies for human PBC. (HEPATOLOGY 2009;50:1494-1500.)