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

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.
AuthorsJohn R Klune, Rajeev Dhupar, Shoko Kimura, Shinya Ueki, Jon Cardinal, Atsunori Nakao, Gary Nace, John Evankovich, Noriko Murase, Allan Tsung, David A Geller
JournalAmerican journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 303 Issue 5 Pg. G666-73 (Sep 01 2012) ISSN: 1522-1547 [Electronic] United States
PMID22744333 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • IRF1 protein, human
  • IRF2 protein, human
  • Interferon Regulatory Factor-1
  • Interferon Regulatory Factor-2
Topics
  • Adenoviridae
  • Animals
  • Blotting, Western
  • Cell Culture Techniques
  • Gene Expression
  • Genetic Vectors
  • Hepatocytes (metabolism)
  • Humans
  • Interferon Regulatory Factor-1 (genetics, metabolism)
  • Interferon Regulatory Factor-2 (genetics, metabolism)
  • Liver (metabolism)
  • Liver Transplantation
  • Male
  • Mice
  • Real-Time Polymerase Chain Reaction
  • Reperfusion Injury (metabolism, prevention & control)

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