Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation
Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation
复制标题
DOI：
10.1038/cdd.2012.80
复制
发表时间：
2012-12-01
影响因子：
12.4
通讯作者：
Rossi, A. G.
中科院分区：
文献类型：
--
作者：
Leitch, A. E.;Lucas, C. D.;Rossi, A. G.
终末分化的中性粒细胞寿命短，但却是先天性免疫反应的关键效应细胞，在许多炎症性疾病的发病和传播中起着重要作用。延迟凋亡，这是他们延长寿命的原因，是严重依赖于细胞内存活与促凋亡蛋白的平衡。在这里，我们阐明了细胞周期蛋白依赖性激酶（CDK）抑制剂药物，如R-roscovitine和DRB（5，6-二氯-1-β-D-呋喃核糖基苯并咪唑）介导中性粒细胞凋亡的机制。我们证明（通过微阵列，共聚焦显微镜，凋亡测定和蛋白质印迹法的组合），磷酸化的RNA聚合酶II的CDKs 7和9的抑制R-roscovitine和中性粒细胞的转录能力的具体影响是负责中性粒细胞凋亡。最后，我们表明，DRB的特异性CDK 7和9抑制驱动嗜中性粒细胞显性炎症的解决。因此，我们强调了一种新的机制，控制原发性人类中性粒细胞转录和细胞凋亡，可以通过选择性CDK抑制剂药物来解决已建立的炎症。Cell Death and Differentiation（2012）19，1950-1961; doi：10.1038/cdd.2012.80; 2012年6月29日在线发表
Terminally differentiated neutrophils are short-lived but the key effector cells of the innate immune response, and have aprominent role in the pathogenesis and propagation of many inflammatory diseases. Delayed apoptosis, which is responsible for their extended longevity, is critically dependent on a balance of intracellular survival versus pro-apoptotic proteins. Here, we elucidate the mechanism by which the cyclin-dependent kinase (CDK) inhibitor drugs such as R-roscovitine and DRB (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) mediate neutrophil apoptosis. We demonstrate (by a combination of microarray, confocal microscopy, apoptosis assays and western blotting) that the phosphorylation of RNA polymerase II by CDKs 7 and 9 is inhibited by R-roscovitine and that specific effects on neutrophil transcriptional capacity are responsible for neutrophil apoptosis. Finally, we show that specific CDK7 and 9 inhibition with DRB drives resolution of neutrophil-dominant inflammation. Thus, we highlight a novel mechanism that controls both primary human neutrophil transcription and apoptosis that could be targeted by selective CDK inhibitor drugs to resolve established inflammation. Cell Death and Differentiation (2012) 19, 1950-1961; doi:10.1038/cdd.2012.80; published online 29 June 2012