C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells
C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells
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DOI：
10.1038/cdd.2012.67
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发表时间：
2012-11-01
影响因子：
12.4
通讯作者：
Cardozo, A. K.
中科院分区：
文献类型：
--
作者：
Allagnat, F.;Fukaya, M.;Cardozo, A. K.
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（T1 D）的特征在于胰腺β细胞的自身免疫性破坏。促炎细胞因子是T1 D中β细胞死亡的早期介质。细胞因子诱导ER应激和β细胞中CHOP过表达，但CHOP过表达在苦参碱诱导的β细胞凋亡中的作用仍有争议。我们目前观察到，CHOP敲低（KD）防止了抗凋亡蛋白B细胞淋巴瘤2（Bcl-2）和髓样细胞白血病序列1（Mcl-1）的精氨酸介导的降解，从而减少了执行者半胱天冬酶9和3的切割以及凋亡。核因子-κ B（NF-κ B）是调节β细胞凋亡和炎症的关键转录因子。CHOP KD导致马槟榔碱诱导的NF-κ B活性和参与细胞凋亡和炎症的关键NF-κ B靶基因（包括iNOS、FAS、IRF-7、IL-15、CCL 5和CXCL 10）的表达降低。这是由于I κ B降解减少和p65易位到细胞核。目前的数据表明，CHOP在促进β-细胞死亡方面具有双重作用：（1）CHOP通过促进苦参碱诱导的线粒体凋亡途径直接促进苦参碱诱导的β-细胞凋亡;（2）通过支持NF-κ B活化和随后的细胞因子/趋化因子表达，CHOP可能促进胰岛炎期间单核细胞的凋亡和对胰岛的化学吸引。Cell Death and Differentiation（2012）19，1836-1846; doi：10.1038/cdd.2012.67; 2012年6月1日在线发表
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