Nuclear factor [kappa]B protects pancreatic [beta]-cells from tumor necrosis factor-[alpha]--mediated apoptosis. (Islet Studies)

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