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© 2001 by the American Diabetes Association, Inc.
Inhibition of Cytokine-Induced NF-
B Activation by Adenovirus-Mediated Expression of a NF-B Super-Repressor Prevents ß-Cell Apoptosis
1 Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
2 Division of Digestive Diseases and Nutrition, University of North Carolina, Chapel Hill, North Carolina
Cytokine-induced ß-cell death is an important event in the pathogenesis of type 1 diabetes. The transcription factor nuclear factor-
B (NF-B) is activated by interleukin-1ß (IL-1ß), and its activity promotes the expression of several ß-cell genes, including pro- and anti-apoptotic genes. To elucidate the role of cytokine (IL-1ß + 
-interferon [IFN-])-induced expression of NF-B in ß-cell apoptosis, rat ß-cells were infected with the recombinant adenovirus AdIB(SA)2, which contained a nondegradable mutant form of inhibitory B (IB(SA)2, with S32A and S36A) that locks NF-B in a cytosolic protein complex, preventing its nuclear action. Expression of IB(SA)2 inhibited cytokine-stimulated nuclear translocation and DNA-binding of NF-B. Cytokine-induced gene expression of several NF-B targets, namely inducible nitric oxide synthase, Fas, and manganese superoxide dismutase, was prevented by AdIB(SA)2, as established by reverse transcriptase–polymerase chain reaction, protein blot, and measurement of nitrite in the medium. Finally, ß-cell survival after IL-1ß + IFN- treatment was significantly improved by IB(SA)2 expression, mostly through inhibition of the apoptotic pathway. Based on these findings, we conclude that NF-B activation, under in vitro conditions, has primarily a pro-apoptotic function in ß-cells.
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