Src Family Kinases Modulate the Loss of Endothelial Barrier Function in Response to TNF-α: Crosstalk with p38 Signaling.
Src Family Kinases Modulate the Loss of Endothelial Barrier Function in Response to TNF-α: Crosstalk with p38 Signaling.
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DOI：
10.1371/journal.pone.0161975
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Vincent PA
中科院分区：
文献类型：
--
作者：
Adam AP;Lowery AM;Martino N;Alsaffar H;Vincent PA
在多种细胞因子和生长因子诱导的内皮通透性增加过程中，需要激活Src家族激酶(SFK)信号通路。然而，我们先前已经证明，通过表达显性负性C末端Src Kinase(DN-CSK)来激活内源性SFK并不足以降低内皮细胞黏附连接的完整性。在正常的静脉内皮细胞中已经观察到基础的SFK活性，并且与基础通透性的增加无关。然而，基础的SFK活性被发现有助于增加静脉内皮细胞对炎症介质诱导的渗漏的敏感性。SFK激活是如何做到这一点的，目前还不清楚。在这里，我们表明，sfk的激活使人真皮微血管内皮细胞对低剂量的肿瘤坏死因子-α敏感。用50pg/ml肿瘤坏死因子-α处理表达dN-csk的细胞后，细胞内质网密度降低，肌动蛋白、细胞骨架和粘着斑蛋白发生剧烈变化。这种协同作用不依赖ROCK或NF-κB活性。肿瘤坏死因子-α诱导的p38信号对屏障功能的协同作用是必需的，单独激活p38MAPK也只能在具有活性的SFK的单层中诱导通透性的变化。这些结果表明，内源性sfk水平的激活通过激活p38使内皮屏障对低生理剂量的肿瘤坏死因子-α更敏感，从而导致内皮紧密连接的丧失。
Activation of Src Family Kinase (SFK) signaling is required for the increase in endothelial permeability induced by a variety of cytokines and growth factors. However, we previously demonstrated that activation of endogenous SFKs by expression of dominant negative C-terminal Src Kinase (DN-Csk) is not sufficient to decrease endothelial adherens junction integrity. Basal SFK activity has been observed in normal venular endothelia and was not associated with increased basal permeability. The basal SFK activity however was found to contribute to increased sensitivity of the venular endothelium to inflammatory mediator-induced leakage. How SFK activation achieves this is still not well understood. Here, we show that SFK activation renders human dermal microvascular endothelial cells susceptible to low doses of TNF-α. Treatment of DN-Csk-expressing cells with 50 pg/ml TNF-α induced a loss of TEER as well as drastic changes in the actin cytoskeleton and focal adhesion proteins. This synergistic effect was independent of ROCK or NF-κB activity. TNF-α-induced p38 signaling was required for the synergistic effect on barrier function, and activation of the p38 MAPK alone was also able to induce changes in permeability only in monolayers with active SFKs. These results suggest that the activation of endogenous levels of SFK renders the endothelial barrier more susceptible to low, physiologic doses of TNF-α through activation of p38 which leads to a loss of endothelial tight junctions.
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