the transcription factor cebp delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells转录因子cebp三角洲在胰腺β细胞具有抗凋亡、抗炎作用.pdfVIP

The Transcription Factor C/EBP delta Has Anti-Apoptotic and Anti-Inflammatory Roles in Pancreatic Beta Cells 1 1 1 1 2 Fabrice Moore *, Izortze Santin , Tatiane C. Nogueira , Esteban N. Gurzov , Lorella Marselli , Piero 2 1 Marchetti , Decio L. Eizirik * ´ 1 Laboratory of Experimental Medicine, Universite Libre de Bruxelles, Brussels, Belgium, 2 Metabolic Unit, Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy Abstract In the course of Type 1 diabetes pro-inflammatory cytokines (e.g., IL-1b, IFN-c and TNF-a) produced by islet-infiltrating immune cells modify expression of key gene networks in b-cells, leading to local inflammation and b-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/EBPd) on b-cell apoptosis and production of inflammatory mediators in the rat insulinoma INS-1E cells, in purified primary rat b-cells and in human islets. C/EBPd is expressed and up-regulated in response to the cytokines IL-1b and IFN-c in rat b-cells and human islets. Small interfering RNA-mediated C/EBPd silencing exacerbated IL-1b+IFN-c-induced caspase 9 and 3 cleavage and apoptosis in these cells. C/EBPd 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/EBPd and CHOP or C/EBPd and BIM in do