title: Mild endoplasmic reticulum stress augments the proinflammatory effect of IL-1β in pancreatic rat β-cells via the IRE1α/XBP1s pathway.
abstract: The prevalence of obesity and type 1 diabetes in children is increasing worldwide. Insulin resistance and augmented circulating free fatty acids associated with obesity may cause pancreatic β-cell endoplasmic reticulum (ER) stress. We tested the hypothesis that mild ER stress predisposes β-cells to an exacerbated inflammatory response when exposed to IL-1β or TNF-α, cytokines that contribute to the pathogenesis of type 1 diabetes. INS-1E cells or primary rat β-cells were exposed to a low dose of the ER stressor cyclopiazonic acid (CPA) or free fatty acids, followed by low-dose IL-1β or TNF-α. ER stress signaling was inhibited by small interfering RNA. Cells were evaluated for proinflammatory gene expression by RT-PCR and ELISA, gene reporter activity, p65 activation by immunofluorescence, and apoptosis. CPA pretreatment enhanced IL-1β- induced, but not TNF-α-induced, expression of chemokine (C-C motif) ligand 2, chemokine (C-X-C motif) ligand 1, inducible nitric oxide synthase, and Fas via augmented nuclear factor κB (NF-κB) activation. X-box binding protein 1 (XBP1) and inositol-requiring enzyme 1, but not CCAAT/enhancer binding protein homologous protein, knockdown prevented the CPA-induced exacerbation of NF-κB-dependent genes and decreased IL-1β-induced NF-κB promoter activity. XBP1 modulated NF-κB activity via forkhead box O1 inhibition. In conclusion, rat β-cells facing mild ER stress are sensitized to IL-1β, generating a more intense and protracted inflammatory response through inositol-requiring enzyme 1/XBP1 activation. These observations link β-cell ER stress to the triggering of exacerbated local inflammation.
authors.affiliation: Laboratory of Experimental Medicine, Erasmus Hospital, Université Libre de Bruxelles, B-1070 Brussels, Belgium.
authors.forename: Michela
authors.initials: M
authors.lastname: Miani
authors.forename: Maikel L
authors.initials: ML
authors.lastname: Colli
authors.forename: Laurence
authors.initials: L
authors.lastname: Ladrière
authors.forename: Miriam
authors.initials: M
authors.lastname: Cnop
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D000818:Animals; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases / Q000378:metabolism*; D017930:Genes, Reporter; D007249:Inflammation; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007340:Insulinoma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; C575026:Ern1 protein, rat; D053583:Interleukin-1beta; D009097:Multienzyme Complexes; D016328:NF-kappa B; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605545:Xbp1 protein, rat; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases