Induction of nuclear factor-κB and its downstream genes by TNF-α and IL-1β has a pro-apoptotic role in pancreatic beta cells
- 8 May 2008
- journal article
- research article
- Published by Springer Science and Business Media LLC in Diabetologia
- Vol. 51 (7), 1213-1225
- https://doi.org/10.1007/s00125-008-0999-7
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.Keywords
This publication has 50 references indexed in Scilit:
- Shared Principles in NF-κB SignalingCell, 2008
- Transcriptional Regulation of the Endoplasmic Reticulum Stress Gene Chop in Pancreatic Insulin-Producing CellsDiabetes, 2007
- NF-κB prevents β cell death and autoimmune diabetes in NOD miceProceedings of the National Academy of Sciences of the United States of America, 2007
- Selective Inhibition of Eukaryotic Translation Initiation Factor 2α Dephosphorylation Potentiates Fatty Acid-induced Endoplasmic Reticulum Stress and Causes Pancreatic β-Cell Dysfunction and ApoptosisJournal of Biological Chemistry, 2007
- Nuclear Factor-κB Regulates β-Cell DeathDiabetes, 2006
- IFN-γ sensitizes MIN6N8 insulinoma cells to TNF-α-induced apoptosis by inhibiting NF-κB-mediated XIAP upregulationBiochemical and Biophysical Research Communications, 2005
- Activation of NF-κB by Extracellular Matrix Is Involved in Spreading and Glucose-stimulated Insulin Secretion of Pancreatic Beta CellsJournal of Biological Chemistry, 2005
- Modulation of NF-κB Activity by Exchange of DimersMolecular Cell, 2003
- NF-κB at the crossroads of life and deathNature Immunology, 2002
- Cytokines activate the nuclear factor κB (NF‐κB) and induce nitric oxide production in human pancreatic isletsFEBS Letters, 1996