title: Distinct from its canonical effects, deletion of IL-12p40 induces cholangitis and fibrosis in interleukin-2Rα(-/-) mice.
abstract: The IL-12 family modulates T cell mediated autoimmune diseases and GWAS in PBC have suggested a critical role of IL-12 and its subunits in modulating portal inflammation. We have taken advantage of an aggressive model of portal inflammation and colitis in IL-2Rα(-/-) mice to study the specific role of IL-12 and, in particular, the immunobiology of p40(-/-)IL-2Rα(-/-) mice. Colonies of IL-2Rα(+/-), IL-2Rα(-/-) and p40(-/-)IL-2Rα(-/-) mice were studied for the natural history of immunopathology in liver and colon using histology and immunohistochemistry. Further, to focus on mechanisms, liver, spleen and mesenteric lymph node flow cytometry was employed to identify specific phenotypes; cytokine analysis on inflammatory cell populations was compared between groups. Finally, Real-Time PCR was used to focus on the genes involved in hepatic fibrosis. Surprisingly, p40(-/-)IL-2Rα(-/-) mice manifest more severe portal inflammation and bile duct damage, including signs of portal hypertension and liver fibrosis, but a significant reduction in colitis. Indeed, p40(-/-)IL-2Rα(-/-) mice reveal a profound hepatic CD8(+) T cell infiltrate, whose major component are effector memory cells as well as enhanced hepatic Th1 but reduced Th17 responses. These observations were confirmed by Real-Time PCR analysis of fibrosis-related genes in the liver. Distinct from its canonical effects, IL-12p40 plays a critical role in autoimmune cholangitis, including hepatic fibrosis. These data take on striking significance for any proposed human trials that modulate the IL-12p40 pathway in human PBC.
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Yang
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Hong-Di
authors.initials: HD
authors.lastname: Ma
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Fang-Ting
authors.initials: FT
authors.lastname: Lu
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Tao
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA.
authors.forename: Weici
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Division of Liver Diseases, Mount Sinai Medical Center, New York, NY 10029, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Friedman
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China; Innovation Center for Cell Biology, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230027, China. Electronic address: zxlian@ucdavis.edu.
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002761:Cholangitis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D017353:Gene Deletion; D053762:Interleukin-12 Subunit p40 / Q000235:genetics*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics*; D008103:Liver Cirrhosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D053645:Interleukin-2 Receptor alpha Subunit
keywords: Effector memory cells; Fibrosis; IFN-γ; IL-12p40; Primary biliary cirrhosis