Nuclear Factor κB Protects Pancreatic β-Cells From Tumor Necrosis Factor-α-Mediated Apoptosis

Nuclear Factor κB Protects Pancreatic β-Cells From Tumor Necrosis Factor-α-Mediated Apoptosis Inik Chang , Sunshin Kim , Ja Young Kim , Namjoo Cho , Yun-Hee Kim , Hun Sik Kim , Moon-Kyu Lee , Kwang-Won Kim and Myung-Shik Lee From the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Abstract 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. Footnotes Address correspondence and reprint requests to Myung-Shik Lee, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Kangnam-ku, Seoul 135-710, Korea. E-mail: mslee{at}smc.samsung.co.kr . Received for publication 19 December 2001 and accepted in revised form 2 January 2003. I.C., S.K., and J.Y.K. contributed equally to this work. Ab, antibody; IFN-γ, γ-interferon; IκB, inhibitor of κB; IL, interleukin; MG132, carbobenzoxyl-leucinyl-leucinyl-leucinal-H; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenylte-trazolium bromide; NF, nuclear factor; NMMA, N -monomethyl l -arginine; SR, superrepressor; TNF, tumor necrosis fact