Enhanced autophagy contributes to protective effects of IL-22 against acetaminophen-induced liver injury.
Enhanced autophagy contributes to protective effects of IL-22 against acetaminophen-induced liver injury.
复制标题
增强的自噬有助于 IL-22 对对乙酰氨基酚诱导的肝损伤的保护作用
作者：
Mo R;Lai R;Lu J;Zhuang Y;Zhou T;Jiang S;Ren P;Li Z;Cao Z;Liu Y;Chen L;Xiong L;Wang P;Wang H;Cai W;Xiang X;Bao S;Xie Q
急性或慢性加急性肝功能衰竭是肝脏疾病死亡的主要原因，没有有效的治疗。白细胞介素-22（IL-22）目前正在进行治疗重型酒精性肝炎的临床试验，但其潜在机制仍有待探讨。自噬在减轻肝损伤中起关键作用。本研究的目的是探讨自噬在IL-22介导的对乙酰氨基酚（APAP）诱导的肝损伤的保护作用中的作用。方法：采用APAP致大鼠急性肝损伤模型。向APAP处理的小鼠施用IL-22。将肝细胞与IL-22预孵育，然后暴露于APAP用于体外分析。结果：IL-22给药显著降低APAP攻击小鼠的血清ALT和AST、肝活性氧和肝坏死。APAP处理增加了肝自噬体，这通过IL-22共处理进一步加强。肝脏LC 3-II在APAP给药后中度上调，而AMP活化激酶（p-AMPK）的磷酸化没有明显改变。IL-22预处理显著上调APAP处理小鼠的肝脏LC 3-II和p-AMPK。IL-22还减轻APAP诱导的细胞毒性，并上调LC 3-II和p-AMPK表达在体外培养的肝细胞与APAP处理。当用化合物C（AMPK抑制剂）阻断p-AMPK时，IL-22介导的LC 3-II转化和对APAP诱导的细胞毒性的保护被削弱。结论：AMPK依赖性自噬增强有助于IL-22对APAP诱导的肝损伤的保护作用。
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.