抄録
Liver injury induced by an overdose of acetaminophen (APAP) has been known to be initiated by covalent binding of the reactive N-acetyl-p-benzoquinone imine metabolite to liver target proteins, but factors other than the covalent binding contribute to the severity of the toxicity. The present study focused on the role of cytokines, which are released mainly from liver nonparenchymal cells, on APAP hepatotoxicity in mice. Liver mRNAs of interleukin-6 (IL-6), IL-10 and IL-11, which are considered to suppress inflammatory tissue injury, increased markedly after the administration of hepatotoxic doses of APAP, as did serum levels of the expressed cytokine proteins. Hepatotoxicity of APAP was exaggerated in mice deficient in IL-6 (IL-6 -/- mice) and IL-10 -/- mice as compared with corresponding wild-type mice. Administration recombinant human IL-11 protein prior to the APAP challenge blocked the liver injury. These results demonstrated the protective role of these cytokines against the APAP hepatotoxicity. Increases in liver mRNAs of tumor necrosis factor-α and IL-1β were observed in the APAP-challenged IL-10 -/-mice, but not in IL-6 -/- mice, suggesting that these proinflammatory cytokines are involved in the initiation of APAP-induced liver injury in mice lacking IL-10.
