Rapamycin inhibits cholangiocyte regeneration by blocking interleukin-6-induced activation of signal transducer and activator of transcription 3 after liver transplantation.
Cholangiocyte proliferation is necessary for biliary recovery from cold ischemia and reperfusion injury (CIRI), but there are few studies on its intracellular mechanism. In this process, the role of rapamycin, a new immunosuppressant used in liver transplantation, is still unknown. In order to determine whether rapamycin can depress cholangiocyte regeneration by inhibiting signal transducer and activator of transcription 3 (STAT3) activation, rapamycin (0.05 mg/kg) was administered to rats for 3 days before orthotopic liver transplantation. The results indicated that cholangiocytes responded to extended cold preservation (12 hours) with severe bile duct injures, marked activation of the interleukin-6 (IL-6)/STAT3 signal pathway, and increased expression of cyclin D1 until 7 days after transplantation, and this was followed by compensatory cholangiocyte regeneration. However, rapamycin treatment inhibited STAT3 activation and resulted in decreased cholangiocyte proliferation and delayed biliary recovery after liver transplantation. On the other hand, rapamycin showed no effect on the expression of IL-6. We conclude that the IL-6/STAT3 signal pathway is involved in initiating cholangiocytes to regenerate and repair CIRI. Rapamycin represses cholangiocyte regeneration by inhibiting STAT3 activation, which might have a negative effect on the healing and recovery of bile ducts in grafts with extended cold preservation. Insights gained from this study will be helpful in designing therapy using rapamycin in clinical patients after liver transplantation.
Chen
Li-Ping
LP
Organ Transplant Center, 309 Hospital of the Chinese People's Liberation Army, Beijing, China, Post Code 100091.
Zhang
Qi-Hao
QH
Chen
Geng
G
Qian
Ye-Yong
YY
Shi
Bing-Yi
BY
Dong
Jia-Hong
JH
D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D015925:Cryopreservation; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000188:drug therapy*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism*; D008115:Liver Regeneration / Q000187:drug effects*; D016031:Liver Transplantation; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*
C530106:Ccnd1 protein, rat; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D019938:Cyclin D1; D020123:Sirolimus