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Nuclear Factor B Protects Pancreatic ß-Cells From Tumor Necrosis Factor--Mediated Apoptosis

From the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Recent studies incriminating tumor necrosis factor (TNF)- as the final effector in pancreatic ß-cell death in type 1 diabetes underscore the potential role of TNF--dependent NF-B activation as an important modulator of pancreatic ß-cell death in autoimmune diabetes. Although nuclear factor (NF)-B activation has been implicated in the protection of target cells against apoptosis by a variety of death effectors, its role in pancreatic islet cell death is not clear. We studied the role of NF-B activation in pancreatic islet cell death by using a -interferon (IFN-)/TNF- synergism model we had previously reported. TNF- induced inhibitor of B (IB) degradation and p65 translocation from cytoplasm to nuclei in MIN6N8 insulinoma cells. The NF-B DNA-binding nuclear complex activated by TNF- contained both the p65 and p50 subunit. IFN- pretreatment did not affect TNF--induced NF-B activation. Treatment with a proteasome inhibitor blocked p65 translocation and induced susceptibility to TNF- in otherwise resistant insulinoma cells or primary pancreatic islet cells. Specific inhibition of NF-B activation by adenoviral transduction of IB "superrepressor" also sensitized insulinoma cells and primary islet ß-cells to TNF--induced apoptosis. These results suggest the protective role of NF-B activation against cytokine-mediated pancreatic ß-cell death, contrary to previous reports implicating NF-B as a mediator of pancreatic islet cell death.

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