期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 303, 期 5, 页码 G666-G673出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00050.2012
关键词
interferon regulatory factor-1; liver; transplantation
资金
- National Institutes of Health [AI-081678, DK-62313, GM-52021, DK-071753]
- American College of Surgeons Resident Research Scholarship
- Society of University Surgeons-Ethicon Research Fellowship
Klune JR, Dhupar R, Kimura S, Ueki S, Cardinal J, Nakao A, Nace G, Evankovich J, Murase N, Tsung A, Geller DA. Interferon regulatory factor-2 is protective against hepatic ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 303: G666-G673, 2012. First published June 28, 2012; doi:10.1152/ajpgi.00050.2012.-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, IFN beta, 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.
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