Role of Interleukin-4 in Drug-Induced Liver Disease

我们之前报道过白细胞介素(IL)-4保护小鼠对对乙酰氨基酚诱导的肝损伤（AILI）的易感性，AILI是急性肝衰竭的主要原因。IL-4的肝保护作用至少部分是由于其诱导γ -谷氨酰半胱氨酸连接酶（γ - gcl），这是谷胱甘肽（GSH）合成速率的决定酶，因为IL-4缺乏导致γ - gcl mRNA和蛋白质水平降低，肝脏中GSH水平的长期消耗，并增加对AILI的易感性。此外，在对乙酰氨基酚处理的IL-4缺陷小鼠中，肝脏GSH水平的长期降低至少部分是由于引起持续的肝脏氧化应激和c- jun - n-末端激酶（JNK）信号传导的持续激活和线粒体功能障碍，从而导致AILI的严重程度。

We previously reported that interleukin (IL)-4 protects against susceptibility of mice to acetaminophen-induced liver injury (AILI), the leading cause of acute liver failure. The hepatoprotective effect of IL-4 was due at least in part to its induction of gamma-glutamylcysteine ligase (gamma-GCL), the rate determining enzyme in glutathione (GSH) synthesis, as IL-4 deficiency resulted in decreased mRNA and protein levels of gamma-GCL, prolonged depletion of GSH levels in the liver, and increased susceptibility to AILI. Moreover, the prolonged diminished levels of hepatic GSH seen in acetaminophen-treated IL-4 deficient mice contributed to the severity of AILI at least in part by causing continuous hepatic oxidative stress and resultant sustained activation of c-Jun-N-terminal kinase (JNK) signaling and mitochondrial dysfunction. In contrast to these findings, this year we found that IL-4 enhanced the severity of halothane-induced liver injury in mice by a mechanism that involved the hepatic infiltration of eosinophils. Conclusion: This year we showed that IL-4 can have either a hepatoprotective or hepatoprotoxicant role in DILD that appears to be dependent on the mechanism of DILD. When IL-4 enhances DILD, its mechanism of toxicity may involve the activation and hepatic infiltration of eosinophils, which have long been associated with many cases of DILD without a known function until now. Our findings have clinical implications as polymorphisms in the IL-4 and/or IL-4 receptor genes have been associated with enhanced susceptibility to DILD.