Granulocyte/macrophage colony-stimulating factor causes a paradoxical increase in the BH3-only pro-apoptotic protein Bim in human neutrophils.
Granulocyte/macrophage colony-stimulating factor causes a paradoxical increase in the BH3-only pro-apoptotic protein Bim in human neutrophils.
复制标题
粒细胞/巨噬细胞集落刺激因子导致人中性粒细胞中仅 BH3 的促凋亡蛋白 Bim 反常增加。
DOI：
10.1165/rcmb.2010-0101oc
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发表时间：
2011-06
影响因子：
6.4
通讯作者：
Chilvers ER
中科院分区：
文献类型：
--
作者：
Cowburn AS;Summers C;Dunmore BJ;Farahi N;Hayhoe RP;Print CG;Cook SJ;Chilvers ER
神经细胞凋亡是炎症消退所必需的，但被几种炎症介质延迟。在这样的终末分化细胞中，还不确定这些试剂是否可以通过抗死亡（Bcl-XL，Mcl-1，Bcl 2A 1）或仅BH 3（Bim，Bid，Puma）Bcl 2家族蛋白的转录调节来抑制细胞凋亡。我们报道了GM-CSF和TNFα阻止了中性粒细胞中Mcl-1和Bcl 2A 1的正常时间依赖性丢失，并证明了它们导致了Bcl-XL转录/翻译的NF-κ B依赖性增加。令人惊讶的是，我们发现GM-CSF和TNFα增加和/或维持促凋亡BH 3-only蛋白Bid的mRNA水平，并且GM-CSF对Bim转录和BimEL表达具有类似的NF-κ B依赖性作用。这些发现的体内相关性通过证明GM-CSF是呼吸机相关性肺炎患者肺灌洗液中存在的主要中性粒细胞存活因子以及证实肺中性粒细胞Bim mRNA增加来显示。最后，GM-CSF引起Bim的线粒体定位和表型转换为显示加速的半胱天冬酶-9依赖性凋亡的细胞。这项研究表明，中性粒细胞的生存剂的能力，诱导一个矛盾的增加，促凋亡蛋白Bid和Bim，并表明，这可能有助于快速凋亡的炎症周期的终止。
Neutrophil apoptosis is essential for the resolution of inflammation but delayed by several inflammatory mediators. In such terminally differentiated cells it has been uncertain whether these agents can inhibit apoptosis through transcriptional regulation of anti-death (Bcl-XL, Mcl-1, Bcl2A1) or BH3-only (Bim, Bid, Puma) Bcl2-family proteins. We report that GM-CSF and TNFα prevent the normal time-dependent loss of Mcl-1 and Bcl2A1 in neutrophils and demonstrate that they cause a NF-κB-dependent increase in Bcl-XL transcription/translation. Surprisingly, we show that GM-CSF and TNFα increase and/or maintain mRNA levels for the pro-apoptotic BH3-only protein Bid and that GM-CSF has a similar NF-κB-dependent effect on Bim transcription and BimEL expression. The in-vivo relevance of these findings was shown by the demonstration that GM-CSF is the dominant neutrophil survival factor present in lung lavage from patients with ventilator-associated pneumonia and confirmation of an increase lung neutrophil Bim mRNA. Finally GM-CSF caused mitochondrial location of Bim and a switch in phenotype to a cell that displays accelerated caspase-9-dependent apoptosis. This study demonstrates the capacity of neutrophil survival agents to induce a paradoxical increase in the pro-apoptotic proteins Bid and Bim and suggests that this may function to facilitate rapid apoptosis at the termination of the inflammatory cycle.