Fas-mediated neutrophil apoptosis is accelerated by Bid, Bak, and Bax and inhibited by Bcl-2 and Mcl-1
Fas-mediated neutrophil apoptosis is accelerated by Bid, Bak, and Bax and inhibited by Bcl-2 and Mcl-1
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DOI：
10.1073/pnas.1110358108
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发表时间：
2011-08-09
影响因子：
11.1
通讯作者：
Roberts, Andrew W.
中科院分区：
文献类型：
--
作者：
Croker, Ben A.;O'Donnell, Joanne A.;Roberts, Andrew W.
在免疫反应期间，中性粒细胞必须整合来自多个来源的生存和死亡信号以调节其寿命。激活Bcl-2或死亡受体调节的细胞凋亡途径的信号可以为中性粒细胞提供强大的刺激，使其发生细胞死亡，但它们是否在中性粒细胞中平行或直接相互作用尚不清楚。以前的研究表明，Bcl-2家族蛋白不是Fas诱导的中性粒细胞死亡所必需的，但没有研究它们是否可以调节其快速发生。通过实时细胞成像监测Fas触发的死亡受体通路激活相关的中性粒细胞活力变化率，我们发现Bcl-2相关蛋白Bid、Bax和巴克加速中性粒细胞凋亡，但对细胞死亡不是必需的。Bcl-2或Mcl-1表达的增加阻止了Fas刺激对凋亡的有效诱导，表明Bcl-2调节的凋亡途径可以直接干扰Fas触发的凋亡。Fas已显示在细胞系中启动NF κ B B活化和基因转录，然而基因转录在Fas活化的Bid（-/-）中性粒细胞中不改变，表明细胞凋亡在中性粒细胞中独立于基因转录而发生。Bid对中性粒细胞凋亡动力学的规范影响中性粒细胞IL-1 β产生的幅度，暗示Bcl-2调节途径在控制中性粒细胞对FasL的反应中的功能作用。这些数据表明，内在凋亡途径直接控制Fas触发的中性粒细胞凋亡的动力学。
During immune responses, neutrophils must integrate survival and death signals from multiple sources to regulate their lifespan. Signals that activate either the Bcl-2- or death receptor-regulated apoptosis pathways can provide powerful stimuli for neutrophils to undergo cell death, but whether they act cooperatively in parallel or directly cross-talk in neutrophils is not known. Previous studies suggested that Bcl-2 family proteins are not required for Fas-induced cell death in neutrophils, but did not examine whether they could modulate its rapid onset. By monitoring the rate of change in neutrophil viability associated with activation of the Fas-triggered death receptor pathway using real-time cell imaging, we show that the Bcl-2-related proteins Bid, Bax, and Bak accelerate neutrophil apoptosis but are not essential for cell death. Increased Bcl-2 or Mcl-1 expression prevents efficient induction of apoptosis by Fas stimulation indicating that the Bcl-2-regulated apoptosis pathway can directly interfere with Fas-triggered apoptosis. Fas has been shown to initiate NF kappa B activation and gene transcription in cell lines, however gene transcription is not altered in Fas-activated Bid(-/-) neutrophils, indicating that apoptosis occurs independently of gene transcription in neutrophils. The specification of kinetics of neutrophil apoptosis by Bid impacts on the magnitude of neutrophil IL-1 beta production, implicating a functional role for the Bcl-2-regulated pathway in controlling neutrophil responses to FasL. These data demonstrate that the intrinsic apoptosis pathway directly controls the kinetics of Fas-triggered apoptosis in neutrophils.