Cytoprotective effects of human interleukin-10 gene transfer against necrosis and apoptosis induced by hepatic cold ischemia/reperfusion injury.
BACKGROUND
Apoptosis as well as necrosis may play an important role in hepatic ischemia/reperfusion (I/R) injury. Interleukin 10 (IL-10), a Th2 type cytokine, modulates inflammatory responses by inhibiting the production of proinflammatory cytokines. The study focused on cytoprotective and antiapoptotic pathways to assess mechanisms by which gene transduction of human IL-10 (hIL-10) may renders grafts resistant to the cold I/R injury.


METHODS
Adenoviruses encoding hIL-10 or beta-galactosidase (LacZ) were injected via the superior mesenteric vein into prospective donor animals. The donor liver was harvested 48h after transduction, and stored for 12h at 4 degrees C lactated Ringer's solution prior to being transplanted. Graft survival, liver function, the degree of necrosis and apoptosis, and the molecules of apoptotic networks were assessed.


RESULTS
Ad-hIL-10 pretreatment significantly prolonged the survival of liver grafts by improving liver function, preserving hepatocyte integrity and architecture, and depressing intrahepatic apoptosis and necrosis. In addition, Ad-hIL-10 pretreatment diminished the release of cytochrome c from mitochondria into cytoplasm and caspase-3 activity, with simultaneous up-regulated of antioxidant HO-1 and anti-antiapoptotic Bcl-2 molecules.


CONCLUSIONS
Adenoviral gene transfer of hIL-10 ameliorated cold I/R injury by decreasing hepatic necrosis and apoptosis. The underlying mechanism of cytoprotective effects may at least be involved with the inhibition of caspase-3 activity and mitochondrial cytochrome c release, and the up-regulation of antiapoptotic (Bcl-2) and antioxidant (HO-1) molecules.
Li
Jie-qun
JQ
Department of Organ Transplantation, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
Qi
Hai-zhi
HZ
He
Zhi-jun
ZJ
Hu
Wei
W
Si
Zhong-zhou
ZZ
Li
Yi-ning
YN
Li
Dong-bo
DB
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D003080:Cold Temperature; D003451:Cryoprotective Agents; D045304:Cytochromes c / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D006085:Graft Survival / Q000502:physiology; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics* / Q000276:immunology; D016031:Liver Transplantation; D009336:Necrosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*
D003451:Cryoprotective Agents; C508609:IL10 protein, human; D016753:Interleukin-10; D045304:Cytochromes c