Laboratoire de Médecine Expérimentale, Université Libre de Bruxelles, Brussels, Belgium.
Cell Death Differ. 2012 Nov;19(11):1836-46. doi: 10.1038/cdd.2012.67. Epub 2012 Jun 1.
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.
C/EBP 同源蛋白（CHOP）的诱导被认为是内质网（ER）应激介导的细胞凋亡的关键事件。1 型糖尿病（T1D）的特征是胰腺β细胞的自身免疫破坏。促炎细胞因子是 T1D 中β细胞死亡的早期介质。细胞因子诱导β细胞内质网应激和 CHOP 过表达，但 CHOP 过表达在细胞因子诱导的β细胞凋亡中的作用仍存在争议。我们目前观察到 CHOP 敲低（KD）可防止细胞因子介导的抗凋亡蛋白 B 细胞淋巴瘤 2（Bcl-2）和髓样细胞白血病序列 1（Mcl-1）的降解，从而减少执行器半胱天冬酶 9 和 3 的切割以及细胞凋亡。核因子-κB（NF-κB）是调节β细胞凋亡和炎症的关键转录因子。CHOP KD 导致细胞因子诱导的 NF-κB 活性和参与凋亡和炎症的关键 NF-κB 靶基因的表达减少，包括 iNOS、FAS、IRF-7、IL-15、CCL5 和 CXCL10。这是由于 IκB 降解减少和 p65 向核内易位。本研究数据表明，CHOP 在促进β细胞死亡中具有双重作用：（1）CHOP 通过促进细胞因子诱导的线粒体凋亡途径直接促进细胞因子诱导的β细胞凋亡；（2）通过支持 NF-κB 激活和随后的细胞因子/趋化因子表达，CHOP 可能有助于凋亡和胰岛炎期间单核细胞向胰岛的趋化吸引。
