C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells.

Details

Serval ID
serval:BIB_DC763804A6EE
Type
Article: article from journal or magazin.
Collection
Publications
Title
C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells.
Journal
Cell Death and Differentiation
Author(s)
Allagnat F., Fukaya M., Nogueira T.C., Delaroche D., Welsh N., Marselli L., Marchetti P., Haefliger J.A., Eizirik D.L., Cardozo A.K.
ISSN
1476-5403 (Electronic)
ISSN-L
1350-9047
Publication state
Published
Issued date
2012
Volume
19
Number
11
Pages
1836-1846
Language
english
Notes
Publication types: Journal ArticlePublication Status: ppublish
Abstract
Induction of the C/EBP homologous protein (CHOP) is considered a key event for endoplasmic reticulum (ER) stress-mediated apoptosis. Type 1 diabetes (T1D) is characterized by an autoimmune destruction of the pancreatic β-cells. Pro-inflammatory cytokines are early mediators of β-cell death in T1D. Cytokines induce ER stress and CHOP overexpression in β-cells, but the role for CHOP overexpression in cytokine-induced β-cell apoptosis remains controversial. We presently observed that CHOP knockdown (KD) prevents cytokine-mediated degradation of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1), thereby decreasing the cleavage of executioner caspases 9 and 3, and apoptosis. Nuclear factor-κB (NF-κB) is a crucial transcription factor regulating β-cell apoptosis and inflammation. CHOP KD resulted in reduced cytokine-induced NF-κB activity and expression of key NF-κB target genes involved in apoptosis and inflammation, including iNOS, FAS, IRF-7, IL-15, CCL5 and CXCL10. This was due to decreased IκB degradation and p65 translocation to the nucleus. The present data suggest that CHOP has a dual role in promoting β-cell death: (1) CHOP directly contributes to cytokine-induced β-cell apoptosis by promoting cytokine-induced mitochondrial pathways of apoptosis; and (2) by supporting the NF-κB activation and subsequent cytokine/chemokine expression, CHOP may contribute to apoptosis and the chemo attraction of mononuclear cells to the islets during insulitis.
Pubmed
Web of science
Open Access
Yes
Create date
08/11/2012 19:22
Last modification date
20/08/2019 17:01
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