| Item type |
文献 / Documents(1) |
| 公開日 |
2023-12-01 |
| アクセス権 |
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|
アクセス権 |
open access |
| 資源タイプ |
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資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
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資源タイプ |
journal article |
| 出版社版DOI |
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|
関連識別子 |
https://doi.org/10.1038/s41423-022-00904-y |
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関連名称 |
10.1038/s41423-022-00904-y |
| 出版タイプ |
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|
出版タイプ |
VoR |
|
出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| タイトル |
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|
タイトル |
Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression |
| 著者 |
Shao, Tihong
Leung, Patrick S. C.
Zhang, Weici
常山, 幸一
Ridgway, William M.
Young, Howard A.
Shuai, Zongwen
Ansari, Aftab A.
Gershwin, M. Eric
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| 抄録 |
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内容記述 |
The interferon (IFN) signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of autoimmunity. We have generated a unique murine model named ARE-Del, with chronic overexpression of IFNγ, by altering IFNγ metabolism. Importantly, these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis, including high titers of autoantibodies and portal inflammation. We hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of cholangitis. To study this hypothesis, ARE-Del+/− mice were treated with the JAK1/2 inhibitor ruxolitinib and serially studied. JAK inhibition resulted in a significant reduction in portal inflammation and bile duct damage, associated with a significant reduction in splenic and hepatic CD4+ T cells and CD8+ T cells. Functionally, ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγ and TNF from splenic CD4+ T cells. Additionally, ruxolitinib treatment also decreased the frequencies of germinal center B (GC B) cells and T follicular helper (Tfh) cells and led to lower serological AMA levels. Of note, liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib treatment. Mechanistically, ruxolitinib inhibited the secretion of IL-6, TNF and MCP1 and the expression of STAT1 but promoted the expression of STAT6 in macrophages in vitro, indicating that M1 macrophage polarization to M2 occurred through activation of the STAT6-IRF4 pathway. Our data highlight the significance, both immunologically and clinically, of the JAK/STAT signaling pathway in autoimmune cholangitis. |
| キーワード |
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|
主題 |
Primary biliary cholangitis |
| キーワード |
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|
主題 |
Autoimmunity |
| キーワード |
|
|
主題 |
Interferons |
| キーワード |
|
|
主題 |
Janus Kinase Inhibitors |
| キーワード |
|
|
主題 |
Ruxolitinib |
| 書誌情報 |
en : Cellular & Molecular Immunology
巻 19,
号 10,
p. 1130-1140,
発行日 2022-08-30
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| 収録物ID |
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収録物識別子タイプ |
ISSN |
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収録物識別子 |
16727681 |
| 収録物ID |
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収録物識別子タイプ |
ISSN |
|
収録物識別子 |
20420226 |
| 出版者 |
|
|
出版者 |
Springer Nature |
| 権利情報 |
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|
権利情報 |
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| EID |
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|
識別子 |
395816 |
| 言語 |
|
|
言語 |
eng |
cmi_19_10_1130.pdf (2.71 MB)
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