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ToxSci Advance Access originally published online on July 24, 2009
Toxicological Sciences 2009 111(2):302-310; doi:10.1093/toxsci/kfp165
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Halothane-Induced Liver Injury is Mediated by Interleukin-17 in Mice

Eisuke Kobayashi*, Masanori Kobayashi*, Koichi Tsuneyama{dagger}, Tatsuki Fukami*, Miki Nakajima* and Tsuyoshi Yokoi*,1

* Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan {dagger} Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Sugitani 930-0194, Toyama, Japan

1 To whom all correspondence should be addressed at Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Fax: +81-76-234-4407. E-mail: tyokoi{at}kenroku.kanazawa-u.ac.jp.

Received May 23, 2009; accepted July 21, 2009


  Abstract

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 µg 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.

Key Words: cytokine; MIP-2; neutrophils; helper T cells; prostaglandin E1.


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