期刊
THERANOSTICS
卷 8, 期 15, 页码 4170-4180出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.25798
关键词
acetaminophen; IL-22; autophagy; p62/SQSTM1; liver injury
资金
- National Natural Science Foundation of China [81570535, 81770587, 81600463]
- National Key Programs on Infectious Diseases of China [2017ZX10202202-005-004, 2017ZX10203201-008, 2018ZX09206005-004]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support [20172008]
- Shanghai Three-Year Plan of the Clinical Skills and Innovations [16CR1002A]
- National Clinical Key Specialty Construction Project of China (Infectious Diseases)
- Three-year Action Plan of Public Health in Shanghai [15GW2K0102]
Acute or acute-on-chronic liver failure is a leading cause of death in liver diseases without effective treatment. Interleukin-22 (IL-22) is currently in clinical trials for the treatment of severe alcoholic hepatitis, but the underlying mechanisms remain to be explored. Autophagy plays a critical role in alleviating liver injury. The aim of the current study is to explore the role of autophagy in IL-22-mediated hepato-protective effect against acetaminophen (APAP)-induced liver injury. Methods: A model of acute liver injury induced by APAP was used in vivo. IL-22 was administrated to the APAP-treated mice. Hepatocytes were pre-incubated with IL-22, followed by exposure to APAP for in vitro analyses. Results: IL-22 administration significantly reduced serum ALT and AST, hepatic reactive oxygen species, and liver necrosis in APAP-challenged mice. APAP treatment increased hepatic autophagosomes, which was further intensified by IL-22 co-treatment. Hepatic LC3-II was moderately upregulated after APAP administration without obvious alteration of phosphorylation of AMP-activated kinase (p-AMPK). IL-22 pretreatment significantly upregulated hepatic LC3-II and p-AMPK in APAP-treated mice. IL-22 also alleviated APAP-induced cytotoxicity and upregulated LC3-II and p-AMPK expression in cultured hepatocytes treated with APAP in vitro. When p-AMPK was blocked with compound C (an AMPK inhibitor), IL-22-mediated LC3-II conversion and protection against APAP-induced cytotoxicity was weakened. Conclusions: Enhanced AMPK-dependent autophagy contributes to protective effects of IL-22 against APAP-induced liver injury.
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