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Proapoptotic BH3-Only Protein Bid Is Essential For Death Receptor–Induced Apoptosis of Pancreatic β-Cells

¹ St. Vincent's Institute, Fitzroy, Australia
² Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

Corresponding author: Dr. Helen Thomas, St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria, 3065, Australia. E-mail: hthomas{at}svi.edu.au

Abbreviations: CHX, cycloheximide; CTL, cytotoxic T-lymphocyte; dnFADD, dominant-negative Fas-associated death domain; ER, endoplasmic reticulum; FADD, Fas-associated death domain; FasL, Fas ligand; FLIP, FADD-like IL-1β–converting enzyme inhibitory protein; IFN-, -interferon; IL, interleukin; NMMA, N^G-monomethyl-L-arginine; TNF, tumor necrosis factor; zVAD.fmk, z-Val-Ala-Asp-fluoromethylketone

OBJECTIVE—Apoptosis of pancreatic β-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 β-cell apoptosis.

RESEARCH DESIGN AND 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)-, and proinflammatory cytokines or cytotoxic stimuli that activate the mitochondrial apoptotic pathway (staurosporine, etoposide, -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- 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 β-cells are destroyed.

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