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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2022
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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. |
format | Online Article Text |
id | pubmed-8922149 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
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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