Halothane-induced liver injury is mediated by interleukin-17 in mice.
Drug-induced liver injury is a major problem in drug development and clinical drug therapy. In most cases the mechanisms are still unknown, thus, it is difficult to predict or prevent these reactions. It has been known that halothane, an inhaled anesthetic, induces liver injury. To investigate the mechanisms of halothane-induced liver injury, we used a recently established mouse model of liver injury. The expression of transcription factors and cytokines specific for Th1 and Th2 (helper T cells), respectively, were compared between BALB/c and C57BL/6 mice. The mRNA expression ratios of mouse T-bet(a Th1-specific transcription factor)/GATA-binding protein (GATA-3, a Th2-specific transcription factor) and interferon gamma/interleukin (IL)-10 were lower in BALB/c mice compared with C57BL/6 mice, suggesting that a typical Th1 or Th2-dominant response could not be distinguished in halothane-induced liver injury. We observed increases of the plasma IL-17 level and hepatic macrophage inflammatory protein 2 expression in halothane-administrated BALB/c mice, as well as neutrophil infiltration. Neutralization of IL-17 suppressed the hepatotoxic effect of halothane. Administration of recombinant IL-17 (1 microg per mouse, single ip) to the halothane-treated mice resulted in a remarkable increase of alanine and aspartate aminotransferases. In conclusion, we demonstrated that IL-17 is involved in the halothane-induced liver injury.
Kobayashi
Eisuke
E
Drug Metabolism and Toxicology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Kobayashi
Masanori
M
Tsuneyama
Koichi
K
Fukami
Tatsuki
T
Nakajima
Miki
M
Yokoi
Tsuyoshi
T
D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D001483:Base Sequence; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology*; D016207:Cytokines / Q000235:genetics; D017931:DNA Primers; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006221:Halothane / Q000633:toxicity*; D020381:Interleukin-17 / Q000008:administration & dosage / Q000097:blood / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics
D018685:Anesthetics, Inhalation; D016207:Cytokines; D017931:DNA Primers; D020381:Interleukin-17; D011994:Recombinant Proteins; D014157:Transcription Factors; D015232:Dinoprostone; D006221:Halothane