Cyclin-dependent kinase inhibitors block leukocyte adhesion and migration
Cyclin-dependent kinase inhibitors block leukocyte adhesion and migration
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DOI：
10.4049/jimmunol.180.3.1808
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发表时间：
2008-02-01
影响因子：
4.4
通讯作者：
Schnapp, Lynn M.
中科院分区：
文献类型：
--
作者：
Liu, Li;Schwartz, Barbara;Schnapp, Lynn M.
白细胞运输是一个严格调控的过程，对于适当的炎症反应至关重要。我们现在报道了一种新的粘附途径，该途径允许未刺激的白细胞粘附并通过暴露的内皮基质或高密度配体迁移，我们将这一过程称为配体诱导粘附。这种配体诱导的粘附是整联蛋白介导的，但与佛波酯刺激的粘附相反，它不依赖于小 GTPase Rap-1 活性。相反，我们通过三个独立的证据证明了细胞周期蛋白依赖性激酶 (Cdk) 4 在配体诱导粘附中的关键作用：Cdk 药理学抑制剂的抑制、Cdk4 显性失活结构的抑制以及 Cdk4 小干扰 RNA 的抑制。 Cdk4 的主要底物 Rb 不是配体诱导粘附所必需的，这表明有一种新的 Cdk4 底物参与其中。我们还证明，Cdk4(-/-) 小鼠受伤后肺部淋巴细胞募集受损。 Cdk 抑制剂可以阻断白细胞粘附和迁移的发现可能会扩大这一新兴疗法的临床适应症。
Leukocyte trafficking is a tightly regulated process essential for an appropriate inflammatory response. We now report a new adhesion pathway that allows unstimulated leukocytes to adhere to and migrate through exposed endothelial matrix or high-density ligand, a process we have termed ligand-induced adhesion. This ligand-induced adhesion is integrin mediated, but in contrast to phorbol ester-stimulated adhesion, it is not dependent on the small GTPase Rap-1 activity. Instead, we show a critical role for cyclin-dependent kinase (Cdk) 4 in ligand-induced adhesion by three independent lines of evidence: inhibition by pharmacological inhibitors of Cdk, inhibition by dominant-negative construct of Cdk4, and inhibition by Cdk4 small interfering RNA. The major substrate of Cdk4, Rb, is not required for ligand-induced adhesion, suggesting the involvement of a novel Cdk4 substrate. We also demonstrate that Cdk4(-/-) mice have impaired recruitment of lymphocytes to the lung following injury. The finding that Cdk inhibitors can block leukocyte adhesion and migration may expand the clinical indications for this emerging class of therapeutics.