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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

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The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.

Moore Fabrice F Santin Izortze I Nogueira Tatiane C TC Gurzov Esteban N EN Marselli Lorella L Marchetti Piero P Eizirik Decio L DL

PloS one 20120208 2

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) ...[more]

PMID: 22347430

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Project description:Transcription factor C/EBP-beta regulates a number of physiological responses. During an investigation of the growth-suppressive effects of interferons (IFNs), we noticed that cebpb(-/-) cells fail to undergo apoptosis upon gamma IFN (IFN-gamma) treatment, compared to wild-type controls. To examine the basis for this response, we have performed gene expression profiling of isogenic wild-type and cebpb(-/-) bone marrow macrophages and identified a number of IFN-gamma-regulated genes that are dependent on C/EBP-beta for their expression. These genes are distinct from those regulated by the JAK-STAT pathways. Genes identified in this screen appear to participate in various cellular pathways. Thus, we identify a new pathway through which the IFNs exert their effects on cellular genes through C/EBP-beta. One of these genes is death-associated protein kinase 1 (dapk1). DAPK1 is critical for regulating the cell cycle, apoptosis, and metastasis. Using site-directed mutagenesis, RNA interference, and chromatin immunoprecipitation assays, we show that C/EBP-beta binds to the promoter of dapk1 and is required for the regulation of dapk1. Both mouse dapk1 and human dapk1 exhibited similar dependences on C/EBP-beta for their expression. The expression of the other members of the DAPK family occurred independently of C/EBP-beta. Members of the C/EBP family of transcription factors other than C/EBP-beta did not significantly affect dapk1 expression. We identified two elements in this promoter that respond to C/EBP-beta. One of these is a consensus C/EBP-beta-binding site that constitutively binds to C/EBP-beta. The other element exhibits homology to the cyclic AMP response element/activating transcription factor binding sites. C/EBP-beta binds to this site in an IFN-gamma-dependent manner. Inhibition of ERK1/2 or mutation of an ERK1/2 site in the C/EBP-beta protein suppressed the IFN-gamma-induced response of this promoter. Together, our data show a critical role for C/EBP-beta in a novel IFN-induced cell growth-suppressive pathway via DAPK1.

Dataset Information

The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.

Publications

The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.

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