In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats.
OBJECTIVE
Orthotopic liver transplantation is currently the only curative therapy for chronic end-stage liver disease and acute liver failure. However, a scarcity of cadaveric donors has led to a critical shortage of organs available for transplant. This is further complicated by the prevalence of steatosis in about 13%-50% of donor livers, which is associated with a high risk of dysfunction and primary nonfunction.


METHODS
Steatotic Zucker rat livers and livers from alcohol-fed rats were transplanted into lean control rats. Liver injury, activation of survival signals, and hepatic microcirculation were compared in nontreated and interleukin-6 (IL-6)-treated steatotic isografts.


RESULTS
IL-6 pretreatment of steatotic Zucker rat liver isografts dramatically reduces mortality and liver injury following transplantation. Reperfusion after transplantation induces significant sinusoidal endothelial cell necrapoptosis in steatotic Zucker rat liver isografts, which is prevented by in vitro IL-6 pretreatment. IL-6 treatment activates cell survival signal transducer and activator of transcription factor 3 (STAT3) in hepatocytes and sinusoidal endothelial cells. Laser Doppler imaging and microsphere analyses demonstrate that IL-6 treatment markedly improves hepatic microcirculation, which is impaired in steatotic Zucker rat liver transplants. Finally, in vitro IL-6 treatment of donor livers also markedly reduces mortality associated with fatty liver transplants from alcohol-fed rats.


CONCLUSIONS
IL-6 induces hepatoprotection of steatotic liver isografts via preventing sinusoidal endothelial cell necrapoptosis and consequent amelioration of hepatic microcirculation, and protecting against hepatocyte death. IL-6 pretreatment of steatotic livers may render such allografts useable for clinical transplantation.
Sun
Zhaoli
Z
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Zlsun@jhmi.edu
Klein
Andrew S
AS
Radaeva
Svetlana
S
Hong
Feng
F
El-Assal
Osama
O
Pan
Hong-Na
HN
Jaruga
Barbara
B
Batkai
Sandor
S
Hoshino
Sumito
S
Tian
Zhigang
Z
Kunos
George
G
Diehl
Anna Mae
AM
Gao
Bin
B
D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004727:Endothelium / Q000166:cytology; D000431:Ethanol / Q000494:pharmacology; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery*; D006085:Graft Survival / Q000187:drug effects; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000494:pharmacology*; D008099:Liver / Q000098:blood supply / Q000166:cytology / Q000187:drug effects; D008102:Liver Circulation / Q000187:drug effects; D017093:Liver Failure / Q000188:drug therapy / Q000401:mortality / Q000601:surgery; D016031:Liver Transplantation / Q000401:mortality*; D008833:Microcirculation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D050796:STAT3 Transcription Factor; D015996:Survival Rate; D015534:Trans-Activators / Q000378:metabolism; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D002492:Central Nervous System Depressants; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D051020:bcl-X Protein; D000431:Ethanol