Identification of potential cytokine pathways for therapeutic intervention in murine primary biliary cirrhosis

Kazuhito Kawata, Masanobu Tsuda, Guo-Xiang Yang, Weici Zhang, Hajime Tanaka, Koichi Tsuneyama, Patrick S C Leung, Xiao-Song He, Stuart Knechtle, Aftab A Ansari, Ross Leon Coppel, M Eric Gershwin

Research output: Contribution to journalArticleResearchpeer-review

38 Citations (Scopus)

Abstract

Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, with the most highly directed and specific autoantibody in both murine and human autoimmunity, the anti-mitochondrial autoantibody (AMA). However, therapeutic advances in this disease have lagged behind. Herein we have taken advantage of our unique model of murine PBC in which mice immunized with 2-octynoic acid coupled to BSA (2OA-BSA), a compound identified by quantitative structure activity relationships (QSAR) of human AMA binding, develop an intense inflammatory cholangitis with striking similarities to humans with PBC. In particular, we have constructed several unique gene-deleted mice, including mice deleted of IL-12p40, IL-12p35, IFN-gamma, IL-23p19, IL-17A, IL-17F and IL-22, immunized these animals with 2OA-BSA and followed the natural history of immunopathology to identify key pathways that might provide clues for successful therapy. Our data indicate that whereas both IL-12/Th1 and IL-23/Th17 are involved in cholangitis, it is the IL-12/Th1 signaling pathway that elicits pathology. In fact, deletion of IFN-gamma prevents disease and suppresses autoantibodies. Importantly, deletion of the Th17 cytokines IL-17A and IL-22, but not IL-17F, reduces biliary damage; IL-17A-knockout mice have reduced levels of anti-mitochondrial antibody. We further demonstrate that the production of IFN-gamma is significantly decreased in the liver of IL-23p19(-/-), IL-17A(-/-) and IL-22(-/-) mice compared with controls. However, the ability of T cells to produce IFN-gamma was not affected in Th17 cytokine-deficient mice. Our data indicate that a deficient Th17 pathway suppresses the accumulation of IFN-gamma producing cells in liver during the early phase of cholangitis. In conclusion, whereas IFN-gamma has a pivotal role in the early events involved in the pathogenesis of autoimmune cholangitis induced by 2OA-BSA, the IL-23/Th17 pathway potentiates the effects of IL-12/IFN-gamma-mediated immunopathology.
Original languageEnglish
Article numbere74225
Number of pages11
JournalPLoS ONE
Volume8
Issue number9
DOIs
Publication statusPublished - 2013

Cite this