Hepatic ischemia-reperfusion injury.

24 Interferon regulatory factor-1 (IRF1) is a nuclear transcription factor that induces inflammatory 25 cytokine mediators and contributes to hepatic ischemia-reperfusion injury (I/R). Currently, no 26 strategies to mitigate IRF1-mediated liver damage exist. Interferon regulatory factor 2 (IRF2) is a 27 structurally similar endogenous protein that competes with IRF1 for DNA binding sites in IRF28 responsive target genes and acts as a competitive inhibitor. However, the role of IRF2 in hepatic 29 injury during hypoxic or inflammatory conditions is unknown. In this study, we hypothesize that 30 IRF2 overexpression may mitigate IRF1-mediated I/R damage. Endogenous IRF2 is basally 31 expressed in normal livers, and is mildly increased by ischemia alone. Overexpression of IRF2 32 protects against hepatic warm I/R injury. Further, we demonstrate that IRF2 overexpression 33 limits production of IRF1-dependent pro-inflammatory genes such as IL-12, IFNβ, and iNOS, 34 even in the presence of IRF1 induction. Additionally, isograft liver transplantation with IRF2 35 heterozygote knockout (IRF2) donor grafts with reduced endogenous IRF2 levels experience 36 worse injury following cold I/R during murine orthotopic liver transplant. These findings 37 indicate that endogenous intrahepatic IRF2 protein is protective because the IRF2-deficient liver 38 donor grafts exhibited increased liver damage compared to the wild-type donor grafts. In 39 summary, IRF2 overexpression protects against I/R injury by decreasing IRF1-dependent injury 40 and may represent a novel therapeutic strategy. 41 42 43 44