title: The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.
abstract: In the course of Type 1 diabetes pro-inflammatory cytokines (e.g., IL-1β, IFN-γ and TNF-α) produced by islet-infiltrating immune cells modify expression of key gene networks in β-cells, leading to local inflammation and β-cell apoptosis. Most known cytokine-induced transcription factors have pro-apoptotic effects, and little is known regarding "protective" transcription factors. To this end, we presently evaluated the role of the transcription factor CCAAT/enhancer binding protein delta (C/EBPδ) on β-cell apoptosis and production of inflammatory mediators in the rat insulinoma INS-1E cells, in purified primary rat β-cells and in human islets. C/EBPδ is expressed and up-regulated in response to the cytokines IL-1β and IFN-γ in rat β-cells and human islets. Small interfering RNA-mediated C/EBPδ silencing exacerbated IL-1β+IFN-γ-induced caspase 9 and 3 cleavage and apoptosis in these cells. C/EBPδ deficiency increased the up-regulation of the transcription factor CHOP in response to cytokines, enhancing expression of the pro-apoptotic Bcl-2 family member BIM. Interfering with C/EBPδ and CHOP or C/EBPδ and BIM in double knockdown approaches abrogated the exacerbating effects of C/EBPδ deficiency on cytokine-induced β-cell apoptosis, while C/EBPδ overexpression inhibited BIM expression and partially protected β-cells against IL-1β+IFN-γ-induced apoptosis. Furthermore, C/EBPδ silencing boosted cytokine-induced production of the chemokines CXCL1, 9, 10 and CCL20 in β-cells by hampering IRF-1 up-regulation and increasing STAT1 activation in response to cytokines. These observations identify a novel function of C/EBPδ as a modulatory transcription factor that inhibits the pro-apoptotic and pro-inflammatory gene networks activated by cytokines in pancreatic β-cells.
authors.affiliation: Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium. fmoore@ulb.ac.be
authors.forename: Fabrice
authors.initials: F
authors.lastname: Moore
authors.forename: Izortze
authors.initials: I
authors.lastname: Santin
authors.forename: Tatiane C
authors.initials: TC
authors.lastname: Nogueira
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Gurzov
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D000818:Animals; D017209:Apoptosis; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000502:physiology*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007249:Inflammation; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology*; D007340:Insulinoma; D050856:Interferon Regulatory Factor-1; D051381:Rats; D050794:STAT1 Transcription Factor
chemical_list: C497252:CEBPD protein, human; D016207:Cytokines; D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D051743:CCAAT-Enhancer-Binding Protein-delta