title: Interleukin-17 is involved in alpha-naphthylisothiocyanate-induced liver injury in mice.
abstract: Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. The pathogenesis of DILI usually involves the participation of the parent drug or metabolites that either directly affect the cell biochemistry or elicit an immune response. However, in most cases the mechanisms are unknown. Alpha-naphthylisothiocyanate (ANIT) is known as a hepatotoxicant that causes biliary cell and hepatocyte damage and induces intense neutrophil infiltration in the liver. To investigate whether an immune-mediated mechanism is involved in ANIT-induced liver injury, we examined the plasma AST, ALT and T-Bil levels, hepatic expression of transcriptional factors, cytokines and CXC chemokine genes, plasma IL-17 level and histopathological changes in liver after ANIT administration in mice. Hepatic mRNA expression of retinoid related orphan receptor gamma t (ROR gamma t) and macrophage inflammatory protein (MIP-2) and plasma IL-17 level was significantly increased in ANIT-administered mice as well as the plasma AST, ALT and T-Bil. Neutralization of IL-17 using anti-IL-17 antibody (100 microg/mouse, single i.p.) suppressed the hepatotoxic effect of ANIT. Co-administration of recombinant IL-17 (1 microg/mouse, single i.p.) to ANIT-administered mice resulted in a remarkable increase of the plasma AST, ALT and T-Bil levels. In conclusion, it was firstly demonstrated that IL-17 is involved in the ANIT-induced liver injury in mice.
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Satonori
authors.initials: S
authors.lastname: Higuchi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mizuno
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D020381:Interleukin-17 / Q000008:administration & dosage / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D020381:Interleukin-17; D011994:Recombinant Proteins; D015058:1-Naphthylisothiocyanate