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

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-apo...

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Autores principales:	Fabrice Moore, Izortze Santin, Tatiane C Nogueira, Esteban N Gurzov, Lorella Marselli, Piero Marchetti, Decio L Eizirik
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/765ae8ab58304da79f745ac58395528c
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spelling	oai:doaj.org-article:765ae8ab58304da79f745ac58395528c2021-11-18T07:28:40ZThe transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.1932-620310.1371/journal.pone.0031062https://doaj.org/article/765ae8ab58304da79f745ac58395528c2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22347430/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203In 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.Fabrice MooreIzortze SantinTatiane C NogueiraEsteban N GurzovLorella MarselliPiero MarchettiDecio L EizirikPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 2, p e31062 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Fabrice Moore Izortze Santin Tatiane C Nogueira Esteban N Gurzov Lorella Marselli Piero Marchetti Decio L Eizirik The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.
description	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.
format	article
author	Fabrice Moore Izortze Santin Tatiane C Nogueira Esteban N Gurzov Lorella Marselli Piero Marchetti Decio L Eizirik
author_facet	Fabrice Moore Izortze Santin Tatiane C Nogueira Esteban N Gurzov Lorella Marselli Piero Marchetti Decio L Eizirik
author_sort	Fabrice Moore
title	The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.
title_short	The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.
title_full	The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.
title_fullStr	The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.
title_full_unstemmed	The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.
title_sort	transcription factor c/ebp delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/765ae8ab58304da79f745ac58395528c
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The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.

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