NF-kappa B prevents beta cell death and autoimmune diabetes in NOD mice.
Whereas NF-kappaB has potent antiapoptotic function in most cell types, it was reported that in pancreatic beta cells it serves a proapoptotic function and may contribute to the pathogenesis of autoimmune type 1 diabetes. To investigate the role of beta cell NF-kappaB in autoimmune diabetes, we produced transgenic mice expressing a nondegradable form of IkappaBalpha in pancreatic beta cells (RIP-mIkappaBalpha mice). beta cells of these mice were more susceptible to killing by TNF-alpha plus IFN-gamma but more resistant to IL-1beta plus IFN-gamma than normal beta cells. Similar results were obtained with beta cells lacking IkappaB kinase beta, a protein kinase required for NF-kappaB activation. Inhibition of beta cell NF-kappaB accelerated the development of autoimmune diabetes in nonobese diabetic mice but had no effect on glucose tolerance or serum insulin in C57BL/6 mice, precluding a nonphysiological effect of transgene expression. Development of diabetes after transfer of diabetogenic CD4(+) T cells was accelerated in RIP-mIkappaBalpha/nonobese diabetic mice and was abrogated by anti-TNF therapy. These results suggest that under conditions that resemble autoimmune type 1 diabetes, the dominant effect of NF-kappaB is prevention of TNF-induced apoptosis. This differs from the proapoptotic function of NF-kappaB in IL-1beta-stimulated beta cells.
Kim
Sunshin
S
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Kangnam-ku, Seoul, Korea.
Millet
Isabelle
I
Kim
Hun Sik
HS
Kim
Ja Young
JY
Han
Myoung Sook
MS
Lee
Moon-Kyu
MK
Kim
Kwang-Won
KW
Sherwin
Robert S
RS
Karin
Michael
M
Lee
Myung-Shik
MS
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha