Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Translational Lab of Liver Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Theranostics. 2018 Jul 30;8(15):4170-4180. doi: 10.7150/thno.25798. eCollection 2018.
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. A model of acute liver injury induced by APAP was used . IL-22 was administrated to the APAP-treated mice. Hepatocytes were pre-incubated with IL-22, followed by exposure to APAP for analyses. 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 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. Enhanced AMPK-dependent autophagy contributes to protective effects of IL-22 against APAP-induced liver injury.
急性或慢加急性肝衰竭是无有效治疗手段的肝脏疾病导致死亡的主要原因。白细胞介素 22（IL-22）目前正在进行治疗严重酒精性肝炎的临床试验，但潜在机制仍有待探索。自噬在减轻肝损伤方面起着关键作用。本研究旨在探讨自噬在 IL-22 介导的对乙酰氨基酚（APAP）诱导的肝损伤保护作用中的作用。使用 APAP 诱导的急性肝损伤模型。给 APAP 处理的小鼠施用 IL-22。用 IL-22 孵育肝细胞，然后暴露于 APAP 进行分析。IL-22 给药显著降低了 APAP 挑战小鼠的血清 ALT 和 AST、肝活性氧和肝坏死。APAP 处理增加了肝自噬体，IL-22 共同处理进一步增强了自噬体。APAP 给药后 LC3-II 中度上调，而 AMP 激活的蛋白激酶（p-AMPK）磷酸化无明显改变。IL-22 预处理显著上调了 APAP 处理小鼠的肝 LC3-II 和 p-AMPK。IL-22 还减轻了 APAP 诱导的细胞毒性，并上调了用 APAP 处理的培养肝细胞中的 LC3-II 和 p-AMPK 表达。当用化合物 C（AMPK 抑制剂）阻断 p-AMPK 时，IL-22 介导的 LC3-II 转化和对 APAP 诱导的细胞毒性的保护作用减弱。增强的 AMPK 依赖性自噬有助于 IL-22 对抗 APAP 诱导的肝损伤的保护作用。
