title: Differential modulation by IL-17A of Cholangitis versus Colitis in IL-2Rα deleted mice.
abstract: IFN-γ is a signature Th1 cell associated cytokine critical for the inflammatory response in autoimmunity with both pro-inflammatory and potentially protective functions. IL-17A is the hallmark of T helper 17 (Th17) cell subsets, produced by γδT, CD8+ T, NK and NKT cells. We have taken advantage of our colony of IL-2Rα-/- mice that spontaneously develop both autoimmune cholangitis and inflammatory bowel disease. In this model CD8+ T cells mediate biliary ductular damage, whereas CD4+ T cells mediate induction of colon-specific autoimmunity. Importantly, IL-2Rα-/- mice have high levels of interferon γ (IFN-γ), and interleukin-17A (IL-17A). We produced unique double deletions of mice that were either IL-17A-/-IL-2Rα-/- or IFN-γ-/-IL-2Rα-/- to specifically address the precise role of these two cytokines in the natural history of autoimmune cholangitis and colitis. Of note, deletion of IL-17A in IL-2Rα-/- mice led to more severe liver inflammation, but ameliorated colitis. In contrast, there were no significant changes in the immunopathology of double knock-out IFN-γ-/- IL-2Rα-/- mice, compared to single knock-out IL-2Rα-/- mice with respect to cholangitis or colitis. Furthermore, there was a significant increase in pathogenetic CD8+ T cells in the liver of IL-17A-/-IL-2Rα-/- mice. Our data suggest that while IL-17A plays a protective role in autoimmune cholangitis, it has a pro-inflammatory role in inflammatory bowel disease. These data take on particular significance in the potential use of anti-IL-17A therapy in humans with primary biliary cirrhosis.
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Yang
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.
authors.forename: Fang-Ting
authors.initials: FT
authors.lastname: Lu
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.
authors.forename: Yin-Hu
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati, Cincinnati, OH, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, United States of America.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China; Innovation Center for Cell Biology, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China.
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002761:Cholangitis / Q000235:genetics / Q000378:metabolism*; D003092:Colitis / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit