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A pivotal involvement of IFN-gamma in the pathogenesis of acetaminophen-induced acute liver injury.

In wild-type BALB/c mice, i.p. administration of acetaminophen (APAP; 750 mg/kg) induced intrahepatic IFN-gamma mRNA expression and a marked increase in serum transaminase levels, leading to acute lethality of approximately 45%. Histopathological examination showed centrilobular hepatic necrosis with leukocyte infiltration and a large number of apoptotic hepatocytes 10 and 24 h after APAP challenge. mRNA expression of intercellular adhesion molecule 1, vascular cell adhesion molecule 1, interleukin (IL) 1alpha, IL-1beta, IL-6, tumor necrosis factor alpha, monocyte chemoattractant protein 1, macrophage inflammatory protein (MIP) 1alpha, MIP-2, KC, IP-10, Mig, Fas, and inducible nitric oxide synthase was enhanced in the liver of wild-type mice injected with APAP. To clarify the role of IFN-gamma in this process, IFN-gamma-deficient mice were treated in the same manner. All IFN-gamma-deficient mice survived with reduced serum transaminase elevation and attenuated hepatic necrosis, leukocyte infiltration, and hepatocyte apoptosis. The gene expression of all molecules was significantly attenuated in IFN-gamma-deficient mice. Administration of an anti-IFN-gamma neutralizing antibody even 2 or 8 h after APAP challenge to wild-type mice alleviated APAP-induced liver injury, and all mice survived. Thus, IFN-gamma is responsible for APAP-induced liver injury by mediating leukocyte infiltration, hepatocyte apoptosis, and NO production as well as cytokine and chemokine production. Moreover, immunoneutralization of IFN-gamma may be therapeutically effective for developing APAP-induced liver injury.