title: Deletion of interleukin (IL)-12p35 induces liver fibrosis in dominant-negative TGFβ receptor type II mice.
abstract: Mice with a dominant-negative transforming growth factor β receptor restricted to T cells (dnTGFβRII mice) develop an inflammatory biliary ductular disease that strongly resembles human primary biliary cirrhosis (PBC). Furthermore, deletion of the gene encoding interleukin (IL)-12p40 resulted in a strain (IL-12p40(-/-) dnTGFβRII) with dramatically reduced autoimmune cholangitis. To further investigate the role of the IL-12 cytokine family in dnTGFβRII autoimmune biliary disease, we deleted the gene encoding the IL-12p35 subunit from dnTGFβRII mice, resulting in an IL-12p35(-/-) dnTGFβRII strain which is deficient in two members of the IL-12 family, IL-12 and IL-35. In contrast to IL-12p40(-/-) mice, the IL-12p35(-/-) mice developed liver inflammation and bile duct damage with similar severity but delayed onset as the parental dnTGFβRII mice. The p35(-/-) mice also demonstrated a distinct cytokine profile characterized by a shift from a T-helper 1 (Th1) to a Th17 response. Strikingly, liver fibrosis was frequently observed in IL-12p35(-/-) mice. In conclusion, IL-12p35(-/-) dnTGFβRII mice, histologically and immunologically, reflect key features of PBC, providing a useful generic model to understand the immunopathology of human PBC.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsuda
authors.forename: Weici
authors.initials: W
authors.lastname: Zhang
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Yugo
authors.initials: Y
authors.lastname: Ando
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Kawata
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
authors.forename: Richard
authors.initials: R
authors.lastname: Flavell
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: He
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006520:Hepatitis, Animal / Q000209:etiology / Q000473:pathology; D018664:Interleukin-12 / Q000172:deficiency / Q000502:physiology; D053765:Interleukin-12 Subunit p35 / Q000172:deficiency / Q000235:genetics*; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D008103:Liver Cirrhosis / Q000473:pathology*; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000473:pathology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D018417:Th1 Cells / Q000502:physiology; D058504:Th17 Cells / Q000502:physiology
chemical_list: D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D018125:Receptors, Transforming Growth Factor beta; D018664:Interleukin-12; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II