C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells.
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.
Laboratoire de Médecine Expérimentale, Université Libre de Bruxelles, Brussels, Belgium.
F
F
Allagnat
M
M
Fukaya
T C
TC
Nogueira
D
D
Delaroche
N
N
Welsh
L
L
Marselli
P
P
Marchetti
J A
JA
Haefliger
D L
DL
Eizirik
A K
AK
Cardozo
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D051550:I-kappa B Kinase / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D053583:Interleukin-1beta; C579093:Mcl1 protein, rat; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051742:Transcription Factor CHOP; D007371:Interferon-gamma; D051550:I-kappa B Kinase; D053148:Caspase 3; D053453:Caspase 9