Proapoptotic BH3-only protein Bid is essential for death receptor-induced apoptosis of pancreatic beta-cells.
OBJECTIVE
Apoptosis of pancreatic beta-cells is critical in both diabetes development and failure of islet transplantation. The role in these processes of pro- and antiapoptotic Bcl-2 family proteins, which regulate apoptosis by controlling mitochondrial integrity, remains poorly understood. We investigated the role of the BH3-only protein Bid and the multi-BH domain proapoptotic Bax and Bak, as well as prosurvival Bcl-2, in beta-cell apoptosis.


METHODS
We isolated islets from mice lacking Bid, Bax, or Bak and those overexpressing Bcl-2 and exposed them to Fas ligand, tumor necrosis factor (TNF)-alpha, and proinflammatory cytokines or cytotoxic stimuli that activate the mitochondrial apoptotic pathway (staurosporine, etoposide, gamma-radiation, tunicamycin, and thapsigargin). Nuclear fragmentation was measured by flow cytometry.


RESULTS
Development and function of islets were not affected by loss of Bid, and Bid-deficient islets were as susceptible as wild-type islets to cytotoxic stimuli that cause apoptosis via the mitochondrial pathway. In contrast, Bid-deficient islets and those overexpressing antiapoptotic Bcl-2 were protected from Fas ligand-induced apoptosis. Bid-deficient islets were also resistant to apoptosis induced by TNF-alpha plus cycloheximide and were partially resistant to proinflammatory cytokine-induced death. Loss of the multi-BH domain proapoptotic Bax or Bak protected islets partially from death receptor-induced apoptosis.


CONCLUSIONS
These results demonstrate that Bid is essential for death receptor-induced apoptosis of islets, similar to its demonstrated role in hepatocytes. This indicates that blocking Bid activity may be useful for protection of islets from immune-mediated attack and possibly also in other pathological states in which beta-cells are destroyed.
McKenzie
Mark D
MD
St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria, 3065, Australia.
Carrington
Emma M
EM
Kaufmann
Thomas
T
Strasser
Andreas
A
Huang
David C S
DC
Kay
Thomas W H
TW
Allison
Janette
J
Thomas
Helen E
HE
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D016923:Cell Death; D045304:Cytochromes c / Q000032:analysis; D005951:Glucose Tolerance Test; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D007372:Interferons / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D053218:Receptors, Death Domain / Q000502:physiology*
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D053583:Interleukin-1beta; D019253:Proto-Oncogene Proteins c-bcl-2; D053218:Receptors, Death Domain; D045304:Cytochromes c; D007372:Interferons