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

21 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
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume303
Issue number5
DOIs
Publication statusPublished - Sep 1 2012
Externally publishedYes

Fingerprint

Interferon Regulatory Factor-2
Reperfusion Injury
Liver
Transplants
Liver Transplantation
Wounds and Injuries
Ischemia
Interferon Regulatory Factors
Interferon Regulatory Factor-1
Isogeneic Transplantation
Cold Ischemia
Warm Ischemia
Nitric Oxide Synthase Type II
Interleukin-12
Heterozygote
Genes
Reperfusion
Proteins
Transcription Factors
Binding Sites

Keywords

  • Interferon regulatory factor-1
  • Liver
  • Transplantation

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Interferon regulatory factor-2 is protective against hepatic ischemia-reperfusion injury. / Klune, John R.; Dhupar, Rajeev; Kimura, Shoko; Ueki, Shinya; Cardinal, Jon; Nakao, Atsunori; Nace, Gary; Evankovich, John; Murase, Noriko; Tsung, Allan; Geller, David A.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 303, No. 5, 01.09.2012.

Research output: Contribution to journalArticle

Klune, JR, Dhupar, R, Kimura, S, Ueki, S, Cardinal, J, Nakao, A, Nace, G, Evankovich, J, Murase, N, Tsung, A & Geller, DA 2012, 'Interferon regulatory factor-2 is protective against hepatic ischemia-reperfusion injury', American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 303, no. 5. https://doi.org/10.1152/ajpgi.00050.2012
Klune, John R. ; Dhupar, Rajeev ; Kimura, Shoko ; Ueki, Shinya ; Cardinal, Jon ; Nakao, Atsunori ; Nace, Gary ; Evankovich, John ; Murase, Noriko ; Tsung, Allan ; Geller, David A. / Interferon regulatory factor-2 is protective against hepatic ischemia-reperfusion injury. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2012 ; Vol. 303, No. 5.
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