Inhibition of cytokine-induced NF-kappaB activation by adenovirus-mediated expression of a NF-kappaB super-repressor prevents beta-cell apoptosis.

Henry Heimberg, Yves Heremans, Christian Jobin, Ruth Leemans, Alessandra Cardozo, Martine Darville, Decio Eizirik

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248 Citations (Scopus)

Abstract

Cytokine-induced beta -cell death is an important event in the pathogenesis of type 1 diabetes. The transcription factor nuclear factor-kappaB (NF-kappaB) is activated by interleukin-1 beta (IL-1 beta), and its activity promotes the expression of several beta -cell genes, including pro- and anti-apoptotic genes. To elucidate the role of cytokine (IL-1 beta + gamma -interferon [IFN-gamma])-induced expression of NF-kappaB in beta -cell apoptosis, rat beta -cells were infected with the recombinant adenovirus AdI kappaB((SA)2), which contained a nondegradable mutant form of inhibitory KB(SA)2, a I kappaB((SA)2) with S32A and S36A that locks NF-kappaB in, cytosolic protein complex, preventing its nuclear action. Expression of I kappaB((SA)2) inhibited cytokine-stimulated nuclear translocation and DNA-binding of NF-kappaB. Cytokine-induced gene expression of several NF-kappaB targets, namely inducible nitric oxide synthase, Fas, and manganese superoxide dismutase, was prevented by AdI kappaB((SA)2), as established by reverse transcriptase-polymerase chain reaction, protein blot, and measurement of nitrite in the medium. Finally, beta -cell survival after IL-1 beta + IFN-gamma treatment was significantly improved by I kappaB((SA)2) expression, mostly through inhibition of the apoptotic pathway. Based on these findings, we conclude that NF-kappaB activation, under in vitro conditions, has primarily a pro-apoptotic function in beta -cells.
Original languageEnglish
Pages (from-to)2219-2224
Number of pages6
JournalDiabetes
Volume50
Publication statusPublished - 2001

Bibliographical note

Diabetes, 50, 2219-2224

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