A comprehensive analysis of cytokine-induced and nuclear factor-kappa B-dependent genes in primary rat pancreatic beta-cells

Alessandra Cardozo, Henry Heimberg, Yves Heremans, Ruth Leeman, B Kutlu, Mogens Kruhoffer, Orben Orntoft, Decio Eizirik

Research output: Contribution to journalArticle

256 Citations (Scopus)

Abstract

Type 1 diabetes mellitus results from an autoimmune destruction of pancreatic beta -cells. Cytokines, such as interleukin-1beta and interferon-gamma , are putative mediators of immune-induced beta -cell death and, under in vitro conditions, cause beta -cell apoptosis. We have recently shown that interleukin-1beta + interferon-gamma modifies the expression of >200 genes in beta -cells. Several of these genes are putative targets for the transcription factor nuclear factor-kappa B (NF-kappa B), and in subsequent experiments we showed that NF-kappa B activation is mostly pro-apoptotic in beta -cells. To identify cytokine-induced and NF-kappa B-regulated genes in primary rat beta -cells, we presently combined two experimental approaches: 1) blocking of NF-kappa B activation in cytokine-exposed beta -cells by a recombinant adenovirus (AdIkappa B(SA)2) containing an inhibitor of NF-kappa B alpha (Ikappa Bac) super-repressor (S32A/S36A) and 2) study of gene expression by microarray analysis. We identified 66 cytokine-modified and NF-kappa B-regulated genes in beta -cells. Cytokine-induced NF-kappa B activation decreased Pdx-1 and increased c-Myc expression. This, together with NF-kappa B-dependent inhibition of Glut-2, pro-hormone convertase-1, and Isl-1 expression, probably contributes to the loss of differentiated beta -cell functions. NF-kappa B also regulates several genes encoding for chemokines and cytokines in beta -cells. The present data suggest that NF-kappa B is a key "switch regulator" of transcription factors and gene networks controlling cytokine-induced beta -cell dysfunction and death.
Original languageEnglish
Pages (from-to)48879-48886
Number of pages8
JournalJ. Biol. Chem.
Volume276
Issue number52
Publication statusPublished - 2001

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