Signaling through C/EBP Homologous Protein and Death Receptor 5 and Calpain Activation Differentially Regulate THP-1 Cell Maturation-Dependent Apoptosis Induced by Shiga Toxin Type 1
Signaling through C/EBP Homologous Protein and Death Receptor 5 and Calpain Activation Differentially Regulate THP-1 Cell Maturation-Dependent Apoptosis Induced by Shiga Toxin Type 1
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DOI：
10.1128/iai.00342-10
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发表时间：
2010-08-01
影响因子：
3.1
通讯作者：
Tesh, Vernon L.
中科院分区：
文献类型：
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作者：
Lee, Moo-Seung;Cherla, Rama P.;Tesh, Vernon L.
志贺毒素 (Stxs) 通过激活许多细胞类型的内在和外在途径来诱导细胞凋亡。毒素介导的内质网 (ER) 应激反应激活有助于启动 THP-1 骨髓性白血病细胞的凋亡。 THP-1细胞以细胞成熟依赖性方式对1型志贺毒素（Stx1）作出反应，在未分化状态下经历快速凋亡，但在分化细胞中减少和延迟凋亡。细胞凋亡的发生与钙蛋白酶激活以及 C/EBP 同源蛋白 (CHOP)、Bcl-2 家族成员和死亡受体 5 (DR5) 表达的变化有关。肿瘤坏死因子 (TNF) 相关凋亡诱导配体 (TRAIL) 连接 DR5 可激活细胞凋亡的外在途径。我们在此表明，Stx1 处理可增加 TRAIL 和 DR5 的表达。添加外源 TRAIL 可增强 Stx1 诱导的 THP-1 细胞凋亡，而抗 TRAIL 抗体可抑制 Stx1 诱导的细胞凋亡。沉默 CHOP 或 DR5 表达可选择性阻止 caspase 激活、线粒体膜电位丧失以及 Stx1 诱导的巨噬细胞样 THP-1 细胞凋亡。相反，单核 THP-1 细胞中凋亡诱导的快速动力学与钙蛋白酶裂解速率相关。结果表明，CHOP-DR5 信号传导和钙蛋白酶激活对细胞成熟依赖性 Stx1 诱导的细胞凋亡有不同的贡献。抑制这些信号通路可以保护细胞免受 Stx 细胞毒性。
Shiga toxins (Stxs) induce apoptosis via activation of the intrinsic and extrinsic pathways in many cell types. Toxin-mediated activation of the endoplasmic reticulum (ER) stress response was shown to be instrumental in initiating apoptosis in THP-1 myeloid leukemia cells. THP-1 cells responded to Shiga toxin type 1 (Stx1) in a cell maturation-dependent manner, undergoing rapid apoptosis in the undifferentiated state but reduced and delayed apoptosis in differentiated cells. The onset of apoptosis was associated with calpain activation and changes in expression of C/EBP homologous protein (CHOP), Bcl-2 family members, and death receptor 5 (DR5). Ligation of DR5 by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) activates the extrinsic pathway of apoptosis. We show here that expression of TRAIL and DR5 is increased by Stx1 treatment. Addition of exogenous TRAIL enhances, and anti-TRAIL antibodies inhibit, Stx1-induced apoptosis of THP-1 cells. Silencing of CHOP or DR5 expression selectively prevented caspase activation, loss of mitochondrial membrane potential, and Stx1-induced apoptosis of macrophage-like THP-1 cells. In contrast, the rapid kinetics of apoptosis induction in monocytic THP-1 cells correlated with rates of calpain cleavage. The results suggest that CHOP-DR5 signaling and calpain activation differentially contribute to cell maturation-dependent Stx1-induced apoptosis. Inhibition of these signaling pathways may protect cells from Stx cytotoxicity.