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Diabetologia
Published in: Diabetologia 7/2008

01-07-2008 | Article

Induction of nuclear factor-κB and its downstream genes by TNF-α and IL-1β has a pro-apoptotic role in pancreatic beta cells

Authors: F. Ortis, P. Pirot, N. Naamane, A. Y. Kreins, J. Rasschaert, F. Moore, E. Théâtre, C. Verhaeghe, N. E. Magnusson, A. Chariot, T. F. Ørntoft, D. L. Eizirik

Published in: Diabetologia | Issue 7/2008

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Abstract

Aims/hypothesis

IL-1β and TNF-α contribute to pancreatic beta cell death in type 1 diabetes. Both cytokines activate the transcription factor nuclear factor-κB (NF-κB), but recent observations suggest that NF-κB blockade prevents IL-1β + IFN-γ- but not TNF-α + IFN-γ-induced beta cell apoptosis. The aim of the present study was to compare the effects of IL-1β and TNF-α on cell death and the pattern of NF-κB activation and global gene expression in beta cells.

Methods

Cell viability was measured after exposure to IL-1β or to TNF-α alone or in combination with IFN-γ, and blockade of NF-κB activation or protein synthesis. INS-1E cells exposed to IL-1β or TNF-α in time course experiments were used for IκB kinase (IKK) activation assay, detection of p65 NF-κB by immunocytochemistry, real-time RT-PCR and microarray analysis.

Results

Blocking NF-κB activation protected beta cells against IL-1β + IFNγ- or TNFα + IFNγ-induced apoptosis. Blocking de novo protein synthesis did not increase TNF-α- or IL-1β-induced beta cell death, in line with the observations that cytokines induced the expression of the anti-apoptotic genes A20, Iap-2 and Xiap to a similar extent. Microarray analysis of INS-1E cells treated with IL-1β or TNF-α showed similar patterns of gene expression. IL-1β, however, induced a higher rate of expression of NF-κB target genes putatively involved in beta cell dysfunction and death and a stronger activation of the IKK complex, leading to an earlier translocation of NF-κB to the nucleus.

Conclusions/interpretation

NF-κB activation in beta cells has a pro-apoptotic role following exposure not only to IL-1β but also to TNF-α. The more marked beta cell death induced by IL-1β is explained at least in part by higher intensity NF-κB activation, leading to increased transcription of key target genes.
Appendix
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Metadata
Title
Induction of nuclear factor-κB and its downstream genes by TNF-α and IL-1β has a pro-apoptotic role in pancreatic beta cells
Authors
F. Ortis
P. Pirot
N. Naamane
A. Y. Kreins
J. Rasschaert
F. Moore
E. Théâtre
C. Verhaeghe
N. E. Magnusson
A. Chariot
T. F. Ørntoft
D. L. Eizirik
Publication date
01-07-2008
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 7/2008
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-008-0999-7

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