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The Proinflammatory Cytokines IL-18, IL-21, and IFN-γ Differentially Regulate Liver Inflammation and Anti-Mitochondrial Antibody Level in a Murine Model of Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a cholestatic liver disease primarily featured by autoimmune-mediated damage of intrahepatic small- and medium-sized bile ducts. Elevated serum proinflammatory cytokines, serum anti-mitochondrial antibodies (AMAs), liver inflammation, and fibrosis are also hallma...

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Autores principales: Xu, Ya-Fei, Yao, Yuan, Ma, Min, Yang, Shu-Han, Jiang, Peng, Wang, Jinjun, Tsuneyama, Koichi, Wang, Chan, Liu, Xiangdong, Li, Liang, Lian, Zhe-Xiong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8922149/
https://www.ncbi.nlm.nih.gov/pubmed/35300072
http://dx.doi.org/10.1155/2022/7111445
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author Xu, Ya-Fei
Yao, Yuan
Ma, Min
Yang, Shu-Han
Jiang, Peng
Wang, Jinjun
Tsuneyama, Koichi
Wang, Chan
Liu, Xiangdong
Li, Liang
Lian, Zhe-Xiong
author_facet Xu, Ya-Fei
Yao, Yuan
Ma, Min
Yang, Shu-Han
Jiang, Peng
Wang, Jinjun
Tsuneyama, Koichi
Wang, Chan
Liu, Xiangdong
Li, Liang
Lian, Zhe-Xiong
author_sort Xu, Ya-Fei
collection PubMed
description Primary biliary cholangitis (PBC) is a cholestatic liver disease primarily featured by autoimmune-mediated damage of intrahepatic small- and medium-sized bile ducts. 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-2Rα(−/−) PBC mouse model to investigate the roles of proinflammatory cytokines IL-18, IL-21, and IFN-γ in the onset and progression of PBC. IL-18(−/−), IFN-γ(−/−), 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-2Rα(−/−) mice exhibit similar transcriptomic characters of PBC patients. In p40(−/−)IL-2Rα(−/−) 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-γ 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.
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spelling pubmed-89221492022-03-16 The Proinflammatory Cytokines IL-18, IL-21, and IFN-γ Differentially Regulate Liver Inflammation and Anti-Mitochondrial Antibody Level in a Murine Model of Primary Biliary Cholangitis Xu, Ya-Fei Yao, Yuan Ma, Min Yang, Shu-Han Jiang, Peng Wang, Jinjun Tsuneyama, Koichi Wang, Chan Liu, Xiangdong Li, Liang Lian, Zhe-Xiong J Immunol Res Research Article Primary biliary cholangitis (PBC) is a cholestatic liver disease primarily featured by autoimmune-mediated damage of intrahepatic small- and medium-sized bile ducts. 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-2Rα(−/−) PBC mouse model to investigate the roles of proinflammatory cytokines IL-18, IL-21, and IFN-γ in the onset and progression of PBC. IL-18(−/−), IFN-γ(−/−), 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-2Rα(−/−) mice exhibit similar transcriptomic characters of PBC patients. In p40(−/−)IL-2Rα(−/−) 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-γ 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. Hindawi 2022-03-07 /pmc/articles/PMC8922149/ /pubmed/35300072 http://dx.doi.org/10.1155/2022/7111445 Text en Copyright © 2022 Ya-Fei Xu et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Xu, Ya-Fei
Yao, Yuan
Ma, Min
Yang, Shu-Han
Jiang, Peng
Wang, Jinjun
Tsuneyama, Koichi
Wang, Chan
Liu, Xiangdong
Li, Liang
Lian, Zhe-Xiong
The Proinflammatory Cytokines IL-18, IL-21, and IFN-γ Differentially Regulate Liver Inflammation and Anti-Mitochondrial Antibody Level in a Murine Model of Primary Biliary Cholangitis
title The Proinflammatory Cytokines IL-18, IL-21, and IFN-γ Differentially Regulate Liver Inflammation and Anti-Mitochondrial Antibody Level in a Murine Model of Primary Biliary Cholangitis
title_full The Proinflammatory Cytokines IL-18, IL-21, and IFN-γ Differentially Regulate Liver Inflammation and Anti-Mitochondrial Antibody Level in a Murine Model of Primary Biliary Cholangitis
title_fullStr The Proinflammatory Cytokines IL-18, IL-21, and IFN-γ Differentially Regulate Liver Inflammation and Anti-Mitochondrial Antibody Level in a Murine Model of Primary Biliary Cholangitis
title_full_unstemmed The Proinflammatory Cytokines IL-18, IL-21, and IFN-γ Differentially Regulate Liver Inflammation and Anti-Mitochondrial Antibody Level in a Murine Model of Primary Biliary Cholangitis
title_short The Proinflammatory Cytokines IL-18, IL-21, and IFN-γ Differentially Regulate Liver Inflammation and Anti-Mitochondrial Antibody Level in a Murine Model of Primary Biliary Cholangitis
title_sort proinflammatory cytokines il-18, il-21, and ifn-γ differentially regulate liver inflammation and anti-mitochondrial antibody level in a murine model of primary biliary cholangitis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8922149/
https://www.ncbi.nlm.nih.gov/pubmed/35300072
http://dx.doi.org/10.1155/2022/7111445
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