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.
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Authors | John R Klune, Rajeev Dhupar, Shoko Kimura, Shinya Ueki, Jon Cardinal, Atsunori Nakao, Gary Nace, John Evankovich, Noriko Murase, Allan Tsung, David A Geller |
Journal | American 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 |
PMID | 22744333
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- IRF1 protein, human
- IRF2 protein, human
- Interferon Regulatory Factor-1
- Interferon Regulatory Factor-2
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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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