Involvement of cytokines in drug-induced liver injury

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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.