Role of Interleukin-4 in Drug-Induced Liver Disease

我们之前曾报道，白介素4可以预防小鼠对醋氨酚诱导的肝损伤(AILI)的易感性，AILI是导致急性肝功能衰竭的主要原因。IL-4的保肝作用至少部分是由于其诱导了谷胱甘肽(GSH)合成的决定酶--γ-谷氨酰半胱氨酸连接酶(Gamma-Glamylcysteine Ligase，GCL)，因为IL-4缺乏会导致γ-GCL的mRNA和蛋白水平降低，肝脏中GSH水平的耗竭时间延长，从而增加对ALI的易感性。此外，在醋氨酚治疗的IL-4缺陷小鼠中，肝脏GSH水平的长期下降至少部分是通过导致持续的肝脏氧化应激以及由此导致的c-Jun-N末端激酶(JNK)信号的持续激活和线粒体功能障碍而导致AILI的严重程度。 与这些发现相反，今年我们发现IL-4通过参与嗜酸性粒细胞在肝脏的渗透，增加了氟烷诱导的小鼠肝损伤的严重程度。 结论：今年我们发现IL-4对DILD既有保护肝脏的作用，也有促肝毒性的作用，这似乎依赖于DILD的机制。当IL-4促进DILD时，其毒性机制可能涉及嗜酸性粒细胞的激活和肝脏的渗透，长期以来，嗜酸性粒细胞一直与许多功能不明的DILD病例有关。我们的发现具有临床意义，因为IL-4和/或IL-4受体基因的多态与DILD的易感性增加有关。

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.