TY - JOUR
T1 - The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells
AU - Moore, Fabrice
AU - Santin, Izortze
AU - Nogueira, Tatiane C
AU - Gurzov, Esteban
AU - Marselli, Lorella
AU - Marchetti, Piero
AU - Eizirik, Decio L
PY - 2012
Y1 - 2012
N2 - In the course of Type 1 diabetes pro-inflammatory cytokines (e.g., IL-1beta, IFN-gamma and TNF-alpha) produced by islet-infiltrating immune cells modify expression of key gene networks in beta-cells, leading to local inflammation and beta-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/EBPdelta) on beta-cell apoptosis and production of inflammatory mediators in the rat insulinoma INS-1E cells, in purified primary rat beta-cells and in human islets. C/EBPdelta is expressed and up-regulated in response to the cytokines IL-1beta and IFN-gamma in rat beta-cells and human islets. Small interfering RNA-mediated C/EBPdelta silencing exacerbated IL-1beta+IFN-gamma-induced caspase 9 and 3 cleavage and apoptosis in these cells. C/EBPdelta 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/EBPdelta and CHOP or C/EBPdelta and BIM in double knockdown approaches abrogated the exacerbating effects of C/EBPdelta deficiency on cytokine-induced beta-cell apoptosis, while C/EBPdelta overexpression inhibited BIM expression and partially protected beta-cells against IL-1beta+IFN-gamma-induced apoptosis. Furthermore, C/EBPdelta silencing boosted cytokine-induced production of the chemokines CXCL1, 9, 10 and CCL20 in beta-cells by hampering IRF-1 up-regulation and increasing STAT1 activation in response to cytokines. These observations identify a novel function of C/EBPdelta as a modulatory transcription factor that inhibits the pro-apoptotic and pro-inflammatory gene networks activated by cytokines in pancreatic beta-cells.
AB - In the course of Type 1 diabetes pro-inflammatory cytokines (e.g., IL-1beta, IFN-gamma and TNF-alpha) produced by islet-infiltrating immune cells modify expression of key gene networks in beta-cells, leading to local inflammation and beta-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/EBPdelta) on beta-cell apoptosis and production of inflammatory mediators in the rat insulinoma INS-1E cells, in purified primary rat beta-cells and in human islets. C/EBPdelta is expressed and up-regulated in response to the cytokines IL-1beta and IFN-gamma in rat beta-cells and human islets. Small interfering RNA-mediated C/EBPdelta silencing exacerbated IL-1beta+IFN-gamma-induced caspase 9 and 3 cleavage and apoptosis in these cells. C/EBPdelta 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/EBPdelta and CHOP or C/EBPdelta and BIM in double knockdown approaches abrogated the exacerbating effects of C/EBPdelta deficiency on cytokine-induced beta-cell apoptosis, while C/EBPdelta overexpression inhibited BIM expression and partially protected beta-cells against IL-1beta+IFN-gamma-induced apoptosis. Furthermore, C/EBPdelta silencing boosted cytokine-induced production of the chemokines CXCL1, 9, 10 and CCL20 in beta-cells by hampering IRF-1 up-regulation and increasing STAT1 activation in response to cytokines. These observations identify a novel function of C/EBPdelta as a modulatory transcription factor that inhibits the pro-apoptotic and pro-inflammatory gene networks activated by cytokines in pancreatic beta-cells.
UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22347430
U2 - 10.1371/journal.pone.0031062
DO - 10.1371/journal.pone.0031062
M3 - Article
VL - 71
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 2
M1 - e31062
ER -