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C/EBP homologous pr...
C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in beta-cells
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Allagnat, F. (author)
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Fukaya, M. (author)
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Nogueira, T. C. (author)
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Delaroche, D. (author)
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- Welsh, Nils (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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Marselli, L. (author)
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Marchetti, P. (author)
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Haefliger, J. A. (author)
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Eizirik, D. L. (author)
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Cardozo, A. K. (author)
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(creator_code:org_t)
- 2012-06-01
- 2012
- English.
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In: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 19:11, s. 1836-1846
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https://europepmc.or...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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 beta-cells. Pro-inflammatory cytokines are early mediators of beta-cell death in T1D. Cytokines induce ER stress and CHOP overexpression in beta-cells, but the role for CHOP overexpression in cytokine-induced beta-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-kappa B (NF-kappa B) is a crucial transcription factor regulating beta-cell apoptosis and inflammation. CHOP KD resulted in reduced cytokine-induced NF-kappa B activity and expression of key NF-kappa B target genes involved in apoptosis and inflammation, including iNOS, FAS, IRF-7, IL-15, CCL5 and CXCL10. This was due to decreased I kappa B degradation and p65 translocation to the nucleus. The present data suggest that CHOP has a dual role in promoting beta-cell death: (1) CHOP directly contributes to cytokine-induced beta-cell apoptosis by promoting cytokine-induced mitochondrial pathways of apoptosis; and (2) by supporting the NF-kappa B activation and subsequent cytokine/chemokine expression, CHOP may contribute to apoptosis and the chemo attraction of mononuclear cells to the islets during insulitis. Cell Death and Differentiation (2012) 19, 1836-1846; doi:10.1038/cdd.2012.67; published online 1 June 2012
Keyword
- CHOP
- Bcl-2 proteins
- ER stress
- apoptosis
- pancreatic beta-cell
- inflammation
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Allagnat, F.
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Fukaya, M.
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Nogueira, T. C.
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Delaroche, D.
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Welsh, Nils
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Marselli, L.
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show more...
-
Marchetti, P.
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Haefliger, J. A.
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Eizirik, D. L.
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Cardozo, A. K.
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show less...
- Articles in the publication
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Cell Death and D ...
- By the university
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Uppsala University