Activation of interleukin-6/STAT3 and liver regeneration following transplantation

Background Every liver that is procured, stored, and transplanted experienc es injury from cold ischemia and reperfusion. Most recover quickly, but som e grafts sustain enough injury to result in prolonged organ dysfunction or require retransplantation. The molecular mechanisms involved in early graft function and recovery following cold ischemia and reperfusion (I/R) after liver transplantation have not been well defined. Interleukin (IL)-6 is a c ritical factor in the mitogenic response within the liver, and is important for cell cycle progression and protection from injury. Activation of the l atent transcription factor, STAT3, is dependent on IL-6 release. The role o f the IL-6/STAT3 pathway and hepatocellular regeneration in graft recovery and cell cycle progression following cold ischemia and reperfusion was stud ied in a rat liver transplant orthotopic (OLT) model. Methods. Rat OLT was performed in a syngeneic model. The presence, time cou rse, and magnitude of expression of IL-6, STAT3 activation, and upregulatio n of target immediate early genes were determined in liver grafts with mini mal (<1 h) and prolonged (12 h) cold preservation times followed by transpl antation. Progression of the cell cycle and replication was confirmed by Br dU uptake. Results. Prolonged cold ischemia resulted in increased IL-6 expression and STAT3 activation. This correlated with upregulation of junB, c-fos, c-myc, and c-jun, immediate early genes associated with hepatic regeneration. Exte nsive DNA replication was present in livers with 12-h ischemia, demonstrati ng successful completion of the cell cycle. Conclusions. The participation of the IL-6/STAT3 pathway leading to cell cy cle progression and regeneration is an important component in the recovery of organs immediately following cold preservation and transplantation. (C) 2001 Academic Press.