Hepatocyte NF-kappaB activation is hepatoprotective during ischemia-reperfusion injury and is augmented by ischemic hypothermia.
The present study examined the role of hepatocyte NF-kappaB activation during ischemia-reperfusion injury. Second, we evaluated the effects of ischemic hypothermia on NF-kappaB 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 degrees C, 33 and 35 degrees C, 29 and 33 degrees C or unregulated, where temperature fell to <29 degrees 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 degrees C) being highly protected and the normothermic group (35-37 degrees C) displaying the greatest injury. Inflammation, as measured by production of TNF-alpha and liver recruitment of neutrophils, was greatest in the normothermic groups and lowest in the ischemic hypothermia groups. Interestingly, hepatocyte NF-kappaB activation was highest in the hypothermic group and least in the normothermic group. Paradoxically, degradation of IkappaB proteins, IkappaB-alpha and IkappaB-beta, was greatest in the normothermic group, suggesting an alternate NF-kappaB regulatory mechanism during ischemia-reperfusion injury. Subsequently, we found that NF-kappaB 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-kappaB activation in hepatocytes is a protective response during ischemia-reperfusion and can be augmented by ischemic hypothermia. Furthermore, it appears that Pin1 promotes NF-kappaB p65 protein stability such that decreased expression of Pin1 during ischemia-reperfusion results in p65 degradation, reduced nuclear translocation of NF-kappaB, and enhanced hepatocellular injury.
Kuboki
Satoshi
S
The Laboratory of Trauma, Sepsis and Inflammation Research, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0558, USA.
Okaya
Tomohisa
T
Schuster
Rebecca
R
Blanchard
John
J
Denenberg
Alvin
A
Wong
Hector R
HR
Lentsch
Alex B
AB
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002467:Cell Nucleus / Q000502:physiology; D022781:Hepatocytes / Q000502:physiology*; D007035:Hypothermia / Q000503:physiopathology*; D007511:Ischemia / Q000503:physiopathology*; D008099:Liver / Q000503:physiopathology*; D008102:Liver Circulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000502:physiology; D015427:Reperfusion Injury / Q000517:prevention & control*
D016328:NF-kappa B; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase