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Originally published In Press as doi:10.1074/jbc.M108658200 on October 30, 2001

J. Biol. Chem., Vol. 276, Issue 52, 48879-48886, December 28, 2001
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A Comprehensive Analysis of Cytokine-induced and Nuclear Factor-kappa B-dependent Genes in Primary Rat Pancreatic beta -Cells*

Alessandra K. CardozoDagger , Harry HeimbergDagger , Yves HeremansDagger , Ruth LeemanDagger , Burak KutluDagger , Mogens Kruhøffer§, Torben Ørntoft§, and Décio L. EizirikDagger

From the Dagger  Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium and the § Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, DK-8200 Aarhus N, Denmark

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.

* This work was supported by grants from the Juvenile Diabetes Foundation International, the Fond for Scientific Research Flanders, and the Karen Elisa Jensen Fond.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Gene Expression Unit, Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. Tel.: 32-2-477-4551; Fax: 32-2-477-4545; E-mail: deizirik@mebo.vub.ac.be.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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