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- κ B (NF- κ B) is a crucial transcription factor regulating β -cell apoptosis and inflammation. CHOP KD resulted in reduced cytokine-induced NF- κ B activity and expression of key NF- κ B target genes involved in apoptosis and inflammation, including iNOS, FAS, IRF-7, IL-15, CCL5 and CXCL10 . This was due to decreased I κ B 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- κ B activation and subsequent cytokine/chemokine expression, CHOP may contribute to apoptosis and the chemo attraction of mononuclear cells to the islets during insulitis.