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Essential role for nuclear factor &kgr;B in ischemic preconditioning for ischemia-reperfusion injury of the mouse liver

Background. Ischemic preconditioning protects various organs from subsequent ischemic insult, but the precise mechanisms underlying this phenomenon remain undefined. To investigate the molecular mechanism by which ischemic preconditioning exerts its protective effect, we examined the activity of the transcription factor nuclear factor (NF)-&kgr;B and subsequent inflammatory gene expression. Methods. Mice were used for total hepatic ischemia-reperfusion experiments after subcutaneous transposition of the spleen. Mouse liver was subjected to ischemia for 70 min followed by reperfusion for defined times. Ischemic preconditioning that consisted of 15 min of ischemia and 20 min of reperfusion was performed before 70 min of ischemia. NF-&kgr;B activity was analyzed by electrophoretic mobility shift assay, and the protein and tyrosine phosphorylation levels of inhibitor &kgr;B-&agr; were assessed by Western blot analysis. Semiquantitative reverse-transcriptase polymerase chain reaction was used to analyze tumor necrosis factor (TNF)-&agr; and intercellular adhesion molecule 1 mRNA levels. Results. NF-&kgr;B was activated within 30 min after initiation of reperfusion and remained activated for 4 hr. Ischemic preconditioning attenuated NF-&kgr;B activation after subsequent prolonged ischemia and reperfusion and simultaneously decreased the expression of TNF-&agr; and intercellular adhesion molecule 1 mRNA, the former statistically significantly (P <0.05). Tyrosine phosphorylation of inhibitor &kgr;B-&agr; was decreased in ischemic preconditioned liver. Conclusions. These results indicate that attenuation of NF-&kgr;B activation and subsequent reduction in TNF-&agr; mRNA expression after sustained ischemia play important roles in the protective mechanism of ischemic preconditioning against hepatic ischemia-reperfusion injury.