title: A pivotal involvement of IFN-gamma in the pathogenesis of acetaminophen-induced acute liver injury.
abstract: 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.
authors.affiliation: Division of Environmental Sciences, Forensic and Social Environmental Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishida
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kondo
authors.forename: Tohru
authors.initials: T
authors.lastname: Ohshima
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
mesh_terms: D000082:Acetaminophen; D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004641:Emigration and Immigration; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D007962:Leukocytes / Q000276:immunology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis; D016019:Survival Analysis
chemical_list: D015815:Cell Adhesion Molecules; D003497:Cyclic N-Oxides; D016207:Cytokines; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007093:Imidazoles; D012333:RNA, Messenger; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D000082:Acetaminophen; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019331:NG-Nitroarginine Methyl Ester