Hepatocyte NF-κB activation is hepatoprotective during ischemia-reperfusion injury and is augmented by ischemic hypothermia

Abstract
The present study examined the role of hepatocyte NF-κB activation during ischemia-reperfusion injury. Second, we evaluated the effects of ischemic hypothermia on NF-κB activation and liver injury. C57BL/6 mice underwent 90 min of partial hepatic ischemia and up to 8 h of reperfusion. Body temperature was regulated during the ischemic period between 35 and 37°C, 33 and 35°C, 29 and 33°C or unregulated, where temperature fell to <29°C. Liver injury, as measured by serum alanine aminotransferase as well as liver histopathology, was inversely proportional to regulated body temperature, with the unregulated group (<29°C) being highly protected and the normothermic group (35–37°C) displaying the greatest injury. Inflammation, as measured by production of TNF-α and liver recruitment of neutrophils, was greatest in the normothermic groups and lowest in the ischemic hypothermia groups. Interestingly, hepatocyte NF-κB activation was highest in the hypothermic group and least in the normothermic group. Paradoxically, degradation of IκB proteins, IκB-α and IκB-β, was greatest in the normothermic group, suggesting an alternate NF-κB regulatory mechanism during ischemia-reperfusion injury. Subsequently, we found that NF-κB p65 protein was increasingly degraded in normothermic versus hypothermic groups, and this degradation was specific for hepatocytes and was associated with decreased expression of the peptidyl-prolyl isomerase Pin1. The data suggest that NF-κB activation in hepatocytes is a protective response during ischemia-reperfusion and can be augmented by ischemic hypothermia. Furthermore, it appears that Pin1 promotes NF-κB p65 protein stability such that decreased expression of Pin1 during ischemia-reperfusion results in p65 degradation, reduced nuclear translocation of NF-κB, and enhanced hepatocellular injury.