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

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

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