title: Endoplasmic reticulum stress sensitizes pancreatic beta cells to interleukin-1β-induced apoptosis via Bim/A1 imbalance.
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.
authors.affiliation: Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Miani
authors.forename: J
authors.initials: J
authors.lastname: Barthson
authors.forename: M L
authors.initials: ML
authors.lastname: Colli
authors.forename: F
authors.initials: F
authors.lastname: Brozzi
authors.forename: M
authors.initials: M
authors.lastname: Cnop
authors.forename: D L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D007211:Indoles; D050417:Insulin-Secreting Cells / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: D051017:Apoptosis Regulatory Proteins; C096816:BCL2-related protein A1; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D004268:DNA-Binding Proteins; D007211:Indoles; D053583:Interleukin-1beta; C579093:Mcl1 protein, rat; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605545:Xbp1 protein, rat; C000543:cyclopiazonic acid