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in the pathogenesis of acetaminophen-induced acute liver injury
Division of Environmental Sciences, Forensic and Social Environmental Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan;
* Department of Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine, Osaka, Japan;
Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; and
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
1Correspondence: Division of Environmental Science, Forensic and Social Environmental Medicine, Graduate School of Medical Science, Kanazawa University, 13–1 Takara-machi, Kanazawa 920-8640, Ishikawa, Japan. E-mail: ohshimat{at}med.kanazawa-u.ac.jp
In wild-type BALB/c mice, i.p. administration of acetaminophen (APAP; 750 mg/kg) induced intrahepatic IFN-
mRNA expression and a marked increase in serum transaminase levels, leading to acute lethality of 
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) 1
, IL-1ß, IL-6, tumor necrosis factor , monocyte chemoattractant protein 1, macrophage inflammatory protein (MIP) 1, 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- in this process, IFN--deficient mice were treated in the same manner. All IFN--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--deficient mice. Administration of an anti-IFN- 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- 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- may be therapeutically effective for developing APAP-induced liver injury.—Ishida, Y., Kondo, T., Ohshima, T., Fujiwara, H., Iwakura, Y., Mukaida, N. A pivotal involvement of IFN- in the pathogenesis of acetaminophen-induced acute liver injury.
Key Words: interferon • chemokines • adhesion molecules • nitric oxide synthase
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