Induction of nuclear factor-κB and its downstream genes by TNF-α and IL-1β has a pro-apoptotic role in pancreatic beta cells
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.
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.
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.
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.
- Induction of nuclear factor-κB and its downstream genes by TNF-α and IL-1β has a pro-apoptotic role in pancreatic beta cells
Volume 51, Issue 7 , pp 1213-1225
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- Diabetes mellitus
- Pancreatic beta cells
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- Author Affiliations
- 1. Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Route de Lennik, 808-CP-618, 1070, Brussels, Belgium
- 2. Laboratory of Medical Chemistry and Human Genetics GIGA Research, CHU, Sart-Tilman, Center for Biomedical Integrated Genoproteomics, CHU Sart-Tilman 4000, Liège, Belgium
- 3. Department of Pharmacology, University of Aarhus, Aarhus, Denmark
- 4. Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark