Endoplasmic reticulum stress sensitizes pancreatic beta cells to interleukin-1β-induced apoptosis via Bim/A1 imbalance
Open Access
- 4 July 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 4 (7), e701
- https://doi.org/10.1038/cddis.2013.236
Abstract
We have recently shown that the crosstalk between mild endoplasmic reticulum (ER) stress and low concentrations of the pro-inflammatory cytokine interleukin (IL)-1β exacerbates beta cell inflammatory responses via the IRE1α/XBP1 pathway. We presently investigated whether mild ER stress also sensitizes beta cells to cytokine-induced apoptosis. Cyclopiazonic acid (CPA)-induced ER stress enhanced the IL-1β apoptosis in INS-1E and primary rat beta cells. This was not prevented by XBP1 knockdown (KD), indicating the dissociation between the pathways leading to inflammation and cell death. Analysis of the role of pro- and anti-apoptotic proteins in cytokine-induced apoptosis indicated a central role for the pro-apoptotic BH3 (Bcl-2 homology 3)-only protein Bim (Bcl-2-interacting mediator of cell death), which was counteracted by four anti-apoptotic Bcl-2 (B-cell lymphoma-2) proteins, namely Bcl-2, Bcl-XL, Mcl-1 and A1. CPA+IL-1β-induced beta cell apoptosis was accompanied by increased expression of Bim, particularly the most pro-apoptotic variant, small isoform of Bim (BimS), and decreased expression of A1. Bim silencing protected against CPA+IL-1β-induced apoptosis, whereas A1 KD aggravated cell death. Bim inhibition protected against cell death caused by A1 silencing under all conditions studied. In conclusion, mild ER stress predisposes beta cells to the pro-apoptotic effects of IL-1β by disrupting the balance between pro- and anti-apoptotic Bcl-2 proteins. These findings link ER stress to exacerbated apoptosis during islet inflammation and provide potential mechanistic targets for beta cell protection, namely downregulation of Bim and upregulation of A1.Keywords
This publication has 53 references indexed in Scilit:
- Thioredoxin-Interacting Protein Mediates ER Stress-Induced β Cell Death through Initiation of the InflammasomeCell Metabolism, 2012
- BCL2A1: the underdog in the BCL2 familyCell Death & Differentiation, 2011
- Endoplasmic reticulum stress and pancreatic β-cell deathTrends in Endocrinology & Metabolism, 2011
- Low risk HLA-DQ and increased body mass index in newly diagnosed type 1 diabetes children in the Better Diabetes Diagnosis study in SwedenInternational Journal of Obesity, 2011
- Bcl-xL Retrotranslocates Bax from the Mitochondria into the CytosolCell, 2011
- Apoptosis of human melanoma cells induced by inhibition of B-RAFV600E involves preferential splicing of bimSCell Death & Disease, 2010
- Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to β-cell apoptosisCell Death & Differentiation, 2010
- p53 Up-regulated Modulator of Apoptosis (PUMA) Activation Contributes to Pancreatic β-Cell Apoptosis Induced by Proinflammatory Cytokines and Endoplasmic Reticulum StressJournal of Biological Chemistry, 2010
- Prediction and Pathogenesis in Type 1 DiabetesImmunity, 2010
- The BCL-2 protein family: opposing activities that mediate cell deathNature Reviews Molecular Cell Biology, 2008