Involvement of cytokines in drug-induced liver injury

为了确定药物性肝损伤的致病或抑制介质，我们重点研究了白介素6(IL-6)家族中的细胞因子。在醋氨酚诱导的肝损伤过程中，肝组织IL-6、IL-11和抑瘤素M的mRNA表达增加。对乙酰氨基酚诱导的肝损伤在IL-6基因敲除(KO)小鼠体内聚集，提示IL-6具有保护性调节作用。KO小鼠的肝脏表现出热休克蛋白(HSP)HSP25、HSP32和HSP40的表达减少。因此，我们认为IL-6通过上调这些蛋白发挥作用。另一方面，通过细胞色素P450介导的药物代谢酶活性来监测非类固醇抗炎药(NSAID)所致的肝功能障碍。在消炎痛处理的小鼠中观察到门静脉内毒素的增加。内毒素抵抗的C3H/HeJ小鼠对消炎痛诱导的肝脏P450酶的下调具有抵抗力。这些结果提示非甾体抗炎药所致的肝功能障碍是由内毒素和内毒素刺激的炎性细胞因子介导的。由此可见，细胞因子是参与促进和抑制药物性肝损伤的主要介质。

To determine pathogenic or suppressive mediators in drug-induced liver injury, we focused on cytokines in interleukin-6 (IL-6) family. During development of liver injury after administration of acetaminophen, hepatic mRNA expressions of IL-6, IL-11 and oncostatin M were increased. The acetaminophen-induced liver injury was aggregated in IL-6 knockout (KO) mice, suggesting that IL-6 behaves as a protective modulator. Livers of the KO mice exhibited decreased expressions of heat shock proteins (HSP) HSP25,HSP32,and HSP40. It is thus suggested that IL-6 acts via up-regulation of these proteins. On the other hand, non-steroidal anti-inflammatory drug (NSAID)-induced liver dysfunction was monitored by cytochrome P450-mediated drug-metabolizing enzyme activities. An increase in portal endotoxin was observed in indomethacin-treated mice. The endotoxin resistant C3H/HeJ mice were resistant to indomethacin-induced down-regulation of P450 enzymes in the liver. These results suggests that the NSAID-induced liver dysfunction is mediated by endotoxin and inflammatory cytokines stimulated by the endotoxin. We could thus conclude that cytokines were primary mediators participated in both promotion and suppression of drug-induced liver injury.