AUTOIMMUNE, CHOLESTATIC AND BILIARY DISEASE Deletion of Interleukin-12p40 Suppresses Autoimmune Cholangitis in Dominant Negative Transforming Growth Factor Receptor Type II Mice
AUTOIMMUNE, CHOLESTATIC AND BILIARY DISEASE Deletion of Interleukin-12p40 Suppresses Autoimmune Cholangitis in Dominant Negative Transforming Growth Factor Receptor Type II Mice
复制标题
DOI：
--
复制
发表时间：
2009
影响因子：
2.1
通讯作者：
Katsunori Yoshida;Guo‐Xiang-X. Yang;Weici Zhang;M. Tsuda;K. Tsuneyama;Y. Moritoki;A. Ansari;K. Okazaki;Zhe‐Xiong Lian;R. Coppel;Ian R. Mackay;M. Gershwin
中科院分区：
文献类型：
--
作者：
Katsunori Yoshida;Guo‐Xiang-X. Yang;Weici Zhang;M. Tsuda;K. Tsuneyama;Y. Moritoki;A. Ansari;K. Okazaki;Zhe‐Xiong Lian;R. Coppel;Ian R. Mackay;M. Gershwin
Our laboratory has reported that mice that express a dominant negative form of transforming growth factor receptor restricted to T cells (dnTGF 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 RII mice and IFNKO-dnTGF RII mice. The two colonies of genetically modified mice—and, for purposes of controls, the dnTGF RII mice—were monitored for liver immunopathology, AMAs, and intrahepatic cytokine production. Disease expression in the IFNKO-dnTGF RII mice, including liver immunopathology, were similar to those of dnTGF RII mice, whereas the IL-12p40 KOdnTGF 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 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.)
