The transcription factor interferon regulatory factor-1 mediates liver damage during ischemia-reperfusion injury

Allan Tsung, Michael T. Stang, Atsushi Ikeda, Nathan D. Critchlow, Kunihiko Izuishi, Atsunori Nakao, Meagan H. Chan, Geetha Jeyabalan, John H. Yim, David A. Geller

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62 Citations (Scopus)

Abstract

Hepatic ischemia occurs in the settings of trauma, transplantation, and elective liver resections. The initiating events that account for local organ damage are only partially understood. Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of a number of genes involved in both innate and acquired immunity; however, its function in liver injury is unknown. Therefore, the purpose of this study was to investigate the role of IRF-1 in hepatic ischemia-reperfusion (I/R) injury. In C57BL/6 mice undergoing 60 min of hepatic ischemia, IRF-1 protein expression increased as early as 1 h after reperfusion. IRF-1 knockout mice were significantly protected from hepatic I/R-induced damage compared with their wild-type controls. Hepatic I/R injury resulted in marked activation of the MAP kinase c-Jun NH 2-terminal kinase (JNK) in wild-type mice but not IRF-1 knockout mice. IRF-1 knockout mice also exhibited significantly lower hepatic expression of TNF-α, IL-6, ICAM-1, and inducible nitric oxide synthase (iNOS) mRNA. Adenoviral delivery of IRF-1 into C57BL/6 mice resulted in increased liver damage even without an ischemic insult. This injury was associated with increased JNK activation and hepatic iNOS expression. Because IRF-1 contributed to liver injury, we also examined for inflammatory signals that regulated IRF-1 gene expression in cultured hepatocytes. Whereas IFN-γ and IFN-β were strong inducers of IRF-1 mRNA (>10-fold) in a time- and dose-dependent manner, TNF-α and IL-1β also induced IRF-1 mRNA to a lesser extent (2- to 3-fold). IL-6 and lipopolysaccharide had no effect on IRF-1 expression. This study demonstrates that IRF-1 exerts a harmful role in hepatic I/R injury by modulating the expression of multiple inflammatory mediators. We further show that IRF-1-mediated injury involves the activation of JNK and that hepatocellular IRF-1 expression itself is regulated by specific cytokines.

Original languageEnglish
Pages (from-to)G1261-G1268
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume290
Issue number6
DOIs
Publication statusPublished - Jun 1 2006
Externally publishedYes

Keywords

  • Cytokines
  • Hepatic ischemia
  • Inducible nitric oxide synthase
  • Liver injury
  • c-Jun NH-terminal kinase

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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  • Cite this

    Tsung, A., Stang, M. T., Ikeda, A., Critchlow, N. D., Izuishi, K., Nakao, A., Chan, M. H., Jeyabalan, G., Yim, J. H., & Geller, D. A. (2006). The transcription factor interferon regulatory factor-1 mediates liver damage during ischemia-reperfusion injury. American Journal of Physiology - Gastrointestinal and Liver Physiology, 290(6), G1261-G1268. https://doi.org/10.1152/ajpgi.00460.2005