title: Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor beta receptor type II mice.
abstract: Our laboratory has reported that mice that express a dominant negative form of transforming growth factor beta receptor restricted to T cells (dnTGFbetaRII) 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)-dnTGFbetaRII mice and IFN-gamma KO-dnTGFbetaRII mice. The two colonies of genetically modified mice-and, for purposes of controls, the dnTGFbetaRII mice-were monitored for liver immunopathology, AMAs, and intrahepatic cytokine production. Disease expression in the IFN-gamma KO-dnTGFbetaRII mice, including liver immunopathology, were similar to those of dnTGFbetaRII mice, whereas the IL-12p40 KO-dnTGFbetaRII 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 dnTGFbetaRII controls.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA 95616, USA.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yoshida
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: Weici
authors.initials: W
authors.lastname: Zhang
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsuda
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Yuki
authors.initials: Y
authors.lastname: Moritoki
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Okazaki
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackay
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002761:Cholangitis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000235:genetics* / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
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