Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor β receptor type II mice

Katsunori Yoshida, Guo Xiang Yang, Weici Zhang, Masanobu Tsuda, Koichi Tsuneyama, Yuki Moritoki, Aftab A. Ansari, Kazuichi Okazaki, Zhe Xiong Lian, Ross L. Coppel, Ian R. Mackay, M. Eric Gershwin

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Abstract

Our laboratory has reported that mice that express a dominant negative form of transforming growth factor β receptor restricted to T cells (dnTGFβRII) 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)-dnTGFβRII mice and IFN-γ KO-dnTGFβRII mice. The two colonies of genetically modified mice - and, for purposes of controls, the dnTGFβRII mice - were monitored for liver immunopathology, AMAs, and intrahepatic cytokine production. Disease expression in the IFN-γ KO-dnTGFβRII mice, including liver immunopathology, were similar to those of dnTGFβRII mice, whereas the IL-12p40 KO-dnTGFβRII 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 dnTGFβRII 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.

Original languageEnglish (US)
Pages (from-to)1494-1500
Number of pages7
JournalHepatology
Volume50
Issue number5
DOIs
StatePublished - 2009

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Cholangitis
Growth Factor Receptors
Interleukins
Transforming Growth Factors
Knockout Mice
Biliary Liver Cirrhosis
Autoantibodies
Cytokines
Immunomodulation
Liver
Interleukin-12
Liver Diseases
T-Lymphocytes
Serum

ASJC Scopus subject areas

  • Hepatology

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Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor β receptor type II mice. / Yoshida, Katsunori; Yang, Guo Xiang; Zhang, Weici; Tsuda, Masanobu; Tsuneyama, Koichi; Moritoki, Yuki; Ansari, Aftab A.; Okazaki, Kazuichi; Lian, Zhe Xiong; Coppel, Ross L.; Mackay, Ian R.; Gershwin, M. Eric.

In: Hepatology, Vol. 50, No. 5, 2009, p. 1494-1500.

Research output: Contribution to journalArticle

Yoshida, K, Yang, GX, Zhang, W, Tsuda, M, Tsuneyama, K, Moritoki, Y, Ansari, AA, Okazaki, K, Lian, ZX, Coppel, RL, Mackay, IR & Gershwin, ME 2009, 'Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor β receptor type II mice', Hepatology, vol. 50, no. 5, pp. 1494-1500. https://doi.org/10.1002/hep.23132
Yoshida, Katsunori ; Yang, Guo Xiang ; Zhang, Weici ; Tsuda, Masanobu ; Tsuneyama, Koichi ; Moritoki, Yuki ; Ansari, Aftab A. ; Okazaki, Kazuichi ; Lian, Zhe Xiong ; Coppel, Ross L. ; Mackay, Ian R. ; Gershwin, M. Eric. / Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor β receptor type II mice. In: Hepatology. 2009 ; Vol. 50, No. 5. pp. 1494-1500.
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AU - Yoshida, Katsunori

AU - Yang, Guo Xiang

AU - Zhang, Weici

AU - Tsuda, Masanobu

AU - Tsuneyama, Koichi

AU - Moritoki, Yuki

AU - Ansari, Aftab A.

AU - Okazaki, Kazuichi

AU - Lian, Zhe Xiong

AU - Coppel, Ross L.

AU - Mackay, Ian R.

AU - Gershwin, M. Eric

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N2 - Our laboratory has reported that mice that express a dominant negative form of transforming growth factor β receptor restricted to T cells (dnTGFβRII) 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)-dnTGFβRII mice and IFN-γ KO-dnTGFβRII mice. The two colonies of genetically modified mice - and, for purposes of controls, the dnTGFβRII mice - were monitored for liver immunopathology, AMAs, and intrahepatic cytokine production. Disease expression in the IFN-γ KO-dnTGFβRII mice, including liver immunopathology, were similar to those of dnTGFβRII mice, whereas the IL-12p40 KO-dnTGFβRII 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 dnTGFβRII 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.

AB - Our laboratory has reported that mice that express a dominant negative form of transforming growth factor β receptor restricted to T cells (dnTGFβRII) 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)-dnTGFβRII mice and IFN-γ KO-dnTGFβRII mice. The two colonies of genetically modified mice - and, for purposes of controls, the dnTGFβRII mice - were monitored for liver immunopathology, AMAs, and intrahepatic cytokine production. Disease expression in the IFN-γ KO-dnTGFβRII mice, including liver immunopathology, were similar to those of dnTGFβRII mice, whereas the IL-12p40 KO-dnTGFβRII 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 dnTGFβRII 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.

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