Suppressor of cytokine signaling 1 inhibits apoptosis of islet grafts through caspase 3 and apoptosis-inducing factor pathways in rats.
A significant portion of pancreatic islet grafts can be destroyed by apoptosis, failing to engraft in the early period after transplantation. Recently, we observed that overexpression of suppressor of cytokine signaling 1 (SOCS1) in islet grafts achieved an antiapoptotic effect, prolonging graft survival in a rat transplant model. Caspase 3 is the central executioner caspase that is activated by upstream cascades in a caspase-dependent apoptosis pathway. Apoptosis inducing factor (AIF) is a key protein that can be released from mitochondria, translocating to the nucleus in the caspase-independent apoptosis pathway. In this study, we investigated whether these two pathways were involved in cytoprotection afforded by SOCS1 on islet grafts. We used a chimeric adenovirus vector (Ad5F35-SOCS1) to enhance SOCS1 expression in isolated Sprague-Dawley rat islets, which were transplanted into recipients experiencing streptozotocin-induced diabetes. We analyzed the expressions of active (cleaved) caspase 3 and AIF on islets. The Ad5F35-SOCS1-infected islets with higher SOCS1 expression showed decreased levels of active caspase 3 and intranuclear AIF after treatment with tumor necrosis factor-α and cycloheximide in vitro. The diabetic recipients transplanted with Ad5F35-SOCS1-infected islets showed longer periods of normoglycemia versus recipients transplanted with mock-infected islets (P < .05) due to prolonged graft survival. A histological analysis indicated that the Ad5F35-SOCS1-infected islet grafts displayed decreased caspase 3 activation and AIF translocation (to nucleus) in the early posttransplant period. These results demonstrated that the expression of SOCS1 in islet grafts protected them from apoptosis through caspase 3 dependent and AIF caspase-independent-pathways.
Suo
G J
GJ
Department of Surgery, Shanghai East Hospital, Tongji University, PR China.
Qin
J
J
Zhong
C P
CP
Zhao
Z X
ZX
D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D005822:Genetic Vectors; D007515:Islets of Langerhans / Q000503:physiopathology; D016381:Islets of Langerhans Transplantation / Q000379:methods / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000494:pharmacology*; D014162:Transfection
D051033:Apoptosis Inducing Factor; C491589:Socs1 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053148:Caspase 3