z-VAD-fmk 增强 TNF 刺激的中性粒细胞凋亡是化合物特异性的，不涉及活性氧的产生,Blood

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z-VAD-fmk 增强 TNF 刺激的中性粒细胞凋亡是化合物特异性的，不涉及活性氧的产生
Blood ( IF 21.0 ) Pub Date : 2005-04-01 , DOI: 10.1182/blood-2004-07-2870
Andrew S Cowburn ₁ , Jessica F White , John Deighton , Sarah R Walmsley , Edwin R Chilvers

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在大多数细胞类型中，组成型和配体诱导的细胞凋亡是一个半胱天冬酶依赖性过程。然而，在中性粒细胞中，广谱 caspase 抑制剂 z-VAD-fmk 可增强肿瘤坏死因子-α (TNF α) 诱导的细胞死亡，这已被解释为 caspase 依赖性和非依赖性细胞死亡途径的证据。我们的目标是确定 z-VAD-fmk 在中性粒细胞中作用的特异性并确定潜在的作用机制。虽然确认 z-VAD-fmk (> 100 microM) 增强了 TNF α 诱导的中性粒细胞凋亡，但较低的浓度 (1-30 microM) 完全阻止了 TNF α 刺激的细胞凋亡。Boc-D-fmk（一种类似的广谱 caspase 抑制剂）和 z-IETD-fmk（一种选择性 caspase-8 抑制剂）仅对 TNF α 刺激的细胞凋亡产生浓度依赖性抑制。而且，caspase-9 抑制剂 Ac-LEHD-cmk 对 TNF α 诱导的细胞凋亡没有影响，z-VAD-fmk 和 Boc-D-fmk 抑制 TNF α 刺激的活性氧 (ROS) 生成。这些数据表明，中性粒细胞中 TNF α 诱导的细胞凋亡完全依赖于半胱天冬酶，并使用不依赖线粒体的途径，并且 z-VAD-fmk 的促凋亡作用是化合物特异性的且不依赖于 ROS。

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z-VAD-fmk augmentation of TNF -stimulated neutrophil apoptosis is compound specific and does not involve the generation of reactive oxygen species

In most cell types constitutive and ligand-induced apoptosis is a caspase-dependent process. In neutrophils, however, the broad-spectrum caspase inhibitor z-VAD-fmk enhances tumor necrosis factor-alpha (TNF alpha)-induced cell death, and this has been interpreted as evidence for caspase-dependent and -independent cell death pathways. Our aim was to determine the specificity of the effect of z-VAD-fmk in neutrophils and define the potential mechanism of action. While confirming that z-VAD-fmk (> 100 microM) enhances TNF alpha-induced neutrophil apoptosis, lower concentrations (1-30 microM) completely blocked TNF alpha-stimulated apoptosis. Boc-D-fmk, a similar broad-spectrum caspase inhibitor, and z-IETD-fmk, a selective caspase-8 inhibitor, caused a concentration-dependent inhibition of only TNF alpha-stimulated apoptosis. Moreover, the caspase-9 inhibitor, Ac-LEHD-cmk, had no effect on TNF alpha-induced apoptosis, and z-VAD-fmk and Boc-D-fmk inhibited TNF alpha-stimulated reactive oxygen species (ROS) generation. These data suggest that TNF alpha-induced apoptosis in neutrophils is fully caspase dependent and uses a mitochondrial-independent pathway and that the proapoptotic effects of z-VAD-fmk are compound specific and ROS independent.

更新日期：2005-04-01

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