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Elevated serum proinflammatory cytokines, serum anti-mitochondrial antibodies (AMAs), liver inflammation, and fibrosis are also hallmarks of PBC disease. However, whether the elevated proinflammatory cytokines play a role in autoimmune cholangitis remains unknown. Herein, we utilized the p40-\/-IL-2R\u03b1-\/- PBC mouse model to investigate the roles of proinflammatory cytokines IL-18, IL-21, and IFN-\u03b3 in the onset and progression of PBC. IL-18-\/-, IFN-\u03b3-\/-, and IL-21-\/- mice were crossed with p40-\/-IL-2Ra+\/- mice, respectively, to produce corresponding cytokine-deficient PBC models. Autoantibody level, liver inflammation, and bile duct injury were analyzed. We found that livers from p40-\/-IL-2R\u03b1-\/- mice exhibit similar transcriptomic characters of PBC patients. In p40-\/-IL-2R\u03b1-\/- mice, deletion of IL-18 has no remarkable effect on disease progression, while deletion of IL-21 indicates that it is necessary for AMA production but independent of liver inflammation and cholangitis. IFN-\u03b3 is responsible for both AMA production and liver inflammation in our model. Our results demonstrate that different proinflammatory cytokines can regulate different effector functions in PBC pathogenesis and need to be considered in PBC treatment.<\/jats:p>","DOI":"10.1155\/2022\/7111445","type":"journal-article","created":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T02:35:08Z","timestamp":1646706908000},"page":"1-11","source":"Crossref","is-referenced-by-count":12,"title":["The Proinflammatory Cytokines IL-18, IL-21, and IFN-\u03b3 Differentially Regulate Liver Inflammation and Anti-Mitochondrial Antibody Level in a Murine Model of Primary Biliary Cholangitis"],"prefix":"10.1155","volume":"2022","author":[{"given":"Ya-Fei","family":"Xu","sequence":"first","affiliation":[{"name":"Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Yao","sequence":"additional","affiliation":[{"name":"Guangzhou Digestive Disease Center, Guangzhou First People\u2019s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Ma","sequence":"additional","affiliation":[{"name":"Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Han","family":"Yang","sequence":"additional","affiliation":[{"name":"Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Jiang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjun","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Environmental Science and Engineering, Yangzhou University, Yangzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Tsuneyama","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6208-4818","authenticated-orcid":true,"given":"Xiangdong","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0745-2571","authenticated-orcid":true,"given":"Liang","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial People\u2019s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9525-1421","authenticated-orcid":true,"given":"Zhe-Xiong","family":"Lian","sequence":"additional","affiliation":[{"name":"Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","reference":[{"key":"1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-020712-164014"},{"key":"2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22042"},{"key":"3","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-018-0109-2"},{"key":"4","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2019-318448"},{"key":"5","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21385"},{"key":"6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2014.02.009"},{"issue":"6","key":"7","doi-asserted-by":"crossref","first-page":"3202","DOI":"10.4049\/jimmunol.162.6.3202","article-title":"Development of CD8+ effector T cells is differentially regulated by IL-18 and IL-12","volume":"162","author":"I. 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