Interferon regulatory factor-2 is protective against hepatic ischemia-reperfusion injury

John R. Klune, Rajeev Dhupar, Shoko Kimura, Shinya Ueki, Jon Cardinal, Atsunori Nakao, Gary Nace, John Evankovich, Noriko Murase, Allan Tsung, David A. Geller

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Interferon regulatory factor (IRF)-1 is a nuclear transcription factor that induces inflammatory cytokine mediators and contributes to hepatic ischemia-reperfusion (I/R) injury. No strategies to mitigate IRF1-mediated liver damage exist. IRF2 is a structurally similar endogenous protein that competes with IRF1 for DNA binding sites in IRF-responsive target genes and acts as a competitive inhibitor. However, the role of IRF2 in hepatic injury during hypoxic or inflammatory conditions is unknown. We hypothesize that IRF2 overexpression may mitigate IRF1-mediated I/R damage. Endogenous IRF2 is basally expressed in normal livers and is mildly increased by ischemia alone. Overexpression of IRF2 protects against hepatic warm I/R injury. Furthermore, we demonstrate that IRF2 overexpression limits production of IRF1-dependent proinflammatory genes, such as IL-12, IFNβ, and inducible nitric oxide synthase, even in the presence of IRF1 induction. Additionally, isograft liver transplantation with IRF2 heterozygote knockout (IRF2+/-) donor grafts that have reduced endogenous IRF2 levels results in worse injury following cold I/R during murine orthotopic liver transplantation. These findings indicate that endogenous intrahepatic IRF2 protein is protective, because the IRF2-deficient liver donor grafts exhibited increased liver damage compared with the wild-type donor grafts. In summary, IRF2 overexpression protects against I/R injury by decreasing IRF1- dependent injury and may represent a novel therapeutic strategy.

Original languageEnglish
Pages (from-to)G666-G673
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume303
Issue number5
DOIs
Publication statusPublished - Sep 1 2012
Externally publishedYes

Keywords

  • Interferon regulatory factor-1
  • Liver
  • Transplantation

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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  • Cite this

    Klune, J. R., Dhupar, R., Kimura, S., Ueki, S., Cardinal, J., Nakao, A., Nace, G., Evankovich, J., Murase, N., Tsung, A., & Geller, D. A. (2012). Interferon regulatory factor-2 is protective against hepatic ischemia-reperfusion injury. American Journal of Physiology - Gastrointestinal and Liver Physiology, 303(5), G666-G673. https://doi.org/10.1152/ajpgi.00050.2012