Activation of interleukin-6/STAT3 and liver regeneration following transplantation.
BACKGROUND
Every liver that is procured, stored, and transplanted experiences injury from cold ischemia and reperfusion. Most recover quickly, but some 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 critical factor in the mitogenic response within the liver, and is important for cell cycle progression and protection from injury. Activation of the latent transcription factor, STAT3, is dependent on IL-6 release. The role of the IL-6/STAT3 pathway and hepatocellular regeneration in graft recovery and cell cycle progression following cold ischemia and reperfusion was studied in a rat liver transplant orthotopic (OLT) model. Methods. Rat OLT was performed in a syngeneic model. The presence, time course, and magnitude of expression of IL-6, STAT3 activation, and upregulation of target immediate early genes were determined in liver grafts with minimal (<1 h) and prolonged (12 h) cold preservation times followed by transplantation. Progression of the cell cycle and replication was confirmed by BrdU 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. Extensive DNA replication was present in livers with 12-h ischemia, demonstrating successful completion of the cell cycle.


CONCLUSIONS
The participation of the IL-6/STAT3 pathway leading to cell cycle progression and regeneration is an important component in the recovery of organs immediately following cold preservation and transplantation.
Debonera
F
F
Department of Surgery, University of Pennsylvania, Philadelphia 19104, USA.
Aldeguer
X
X
Shen
X
X
Gelman
A E
AE
Gao
F
F
Que
X
X
Greenbaum
L E
LE
Furth
E E
EE
Taub
R
R
Olthoff
K M
KM
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division; D015925:Cryopreservation; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early / Q000502:physiology; D006085:Graft Survival; D015850:Interleukin-6 / Q000502:physiology*; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008115:Liver Regeneration; D016031:Liver Transplantation; D008297:Male; D011184:Postoperative Period; D051381:Rats; D011917:Rats, Inbred Lew; D050796:STAT3 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
D016207:Cytokines; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; D004247:DNA