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Theranostics 2018; 8(15):4170-4180. doi:10.7150/thno.25798 This issue Cite

Research Paper

Enhanced autophagy contributes to protective effects of IL-22 against acetaminophen-induced liver injury

Ruidong Mo^1,2#, Rongtao Lai^1,2#, Jie Lu^1,2#, Yan Zhuang¹, Tianhui Zhou^1,2, Shaowen Jiang^1,2, Peipei Ren^1,2, Ziqiang Li^1,2, Zhujun Cao^1,2, Yuhan Liu^1,2, Lichang Chen^1,2, Lifu Xiong^1,2, Peng Wang^1,2, Hui Wang¹, Wei Cai¹, Xiaogang Xiang^1,2✉, Shisan Bao^3✉, Qing Xie^1,2✉

1. Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2. Translational Lab of Liver Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
3. Discipline of Pathology, School of Medical Sciences and Bosch Institute, Charles Perkins Centre, The University of Sydney, New South Wales 2006, Australia
^#These authors contributed equally to this work.

✉ Corresponding authors: Qing Xie MD, PhD, Department of Infectious Diseases, Translational Lab of Liver Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Building 36, 197 Ruijin Er Road, Huangpu District, Shanghai, 200025, China. Tel: +86 21 64370045 x 680403; Fax: +86 21 6445 4930; E-mail: xieqingrjhcom, Shisan Bao MD, PhD, Discipline of Pathology, School of Medical Sciences and Bosch Institute, Charles Perkins Centre, The University of Sydney, NSW 2006, Australia. Tel: +61 2 9351 6156; Fax: +61 2 9351 3429; E-mail: bob.baoedu.au and Xiaogang Xiang MD, PhD, Department of Infectious Diseases, Translational Lab of Liver Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Building 36, 197 Ruijin Er Road, Huangpu District, Shanghai, 200025, China. Tel: +86 21 64370045 x 681021; Fax: +86 21 6445 4930; E-mail: shine-xxgcom More

Abstract

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.

Keywords: acetaminophen, IL-22, autophagy, p62/SQSTM1, liver injury.

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