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-1?, IFN-? and TNF-?) produced by islet-infiltrating immune cells modify expression of key gene networks in ?-cells, leading to local inflammation and ?-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/EBP?) on ?-cell apoptosis and production of inflammatory mediators in the rat insulinoma INS-1E cells, in purified primary rat ?-cells and in human islets. C/EBP? is expressed and up-regulated in response to the cytokines IL-1? and IFN-? in rat ?-cells and human islets. Small interfering RNA-mediated C/EBP? silencing exacerbated IL-1?+IFN-?-induced caspase 9 and 3 cleavage and apoptosis in these cells. C/EBP? 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/EBP? and CHOP or C/EBP? and BIM in double knockdown approaches abrogated the exacerbating effects of C/EBP? deficiency on cytokine-induced ?-cell apoptosis, while C/EBP? overexpression inhibited BIM expression and partially protected ?-cells against IL-1?+IFN-?-induced apoptosis. Furthermore, C/EBP? silencing boosted cytokine-induced production of the chemokines CXCL1, 9, 10 and CCL20 in ?-cells by hampering IRF-1 up-regulation and increasing STAT1 activation in response to cytokines. These observations identify a novel function of C/EBP? as a modulatory transcription factor that inhibits the pro-apoptotic and pro-inflammatory gene networks activated by cytokines in pancreatic ?-cells.

SUBMITTER: Moore F 

PROVIDER: S-EPMC3275575 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature