Cdc42 GTPases facilitate TNF-α-mediated secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells.
Cdc42 GTPases facilitate TNF-α-mediated secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells.
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DOI：
10.1111/jns5.12032
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Stubbs EB Jr
中科院分区：
文献类型：
--
作者：
Langert KA;Von Zee CL;Stubbs EB Jr
自身反应性白细胞穿过血神经屏障进入周围神经是格林-巴-罗综合征（GBS）的早期病理标志。肿瘤坏死因子-α (TNF-α)是一种促炎细胞因子，通过上调炎症介质（包括与GBS相关的趋化因子CCL2）的内皮表达来促进跨内皮迁移。我们试图确定TNF-α诱导周围神经微血管内皮细胞（PNMECs）表达和分泌CCL2的机制。静止PNMEC培养中CCL2 mRNA和蛋白的表达极少。相比之下，TNF-α处理的培养物显示CCL2 mRNA和蛋白质含量增加，以及蛋白质分泌增加。辛伐他汀可显著减弱TNF-α诱导的CCL2分泌，但不影响CCL2 mRNA或蛋白的表达。与香叶基焦磷酸香叶基共孵育，而不是焦磷酸法尼基共孵育，可以阻止辛伐他汀的作用。相比之下，用GGTI-298抑制蛋白异戊二烯化，而不使用FTI-277，在体外模拟辛伐他汀的效果，并显着减弱跨内皮迁移。抑制GTPase单体Cdc42，而非Rac1或RhoA-C，可减弱TNF-α介导的CCL2分泌。在GBS期间，TNF-α介导的自身反应性白细胞进入周围神经的运输可能通过Cdc42促进CCL2分泌的机制进行。
Trafficking of autoreactive leukocytes across the blood-nerve barrier and into peripheral nerves is an early pathological hallmark of Guillain-Barré syndrome (GBS). Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, promotes transendothelial migration by up-regulating endothelial expression of inflammatory mediators, including CCL2, a chemokine implicated in GBS. We sought to determine the mechanism by which TNF-α induces expression and secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells (PNMECs). Expression of CCL2 mRNA and protein in quiescent PNMEC cultures was minimal. In contrast, cultures treated with TNF-α exhibited increased CCL2 mRNA and protein content, as well as protein secretion. Simvastatin significantly attenuated TNF-α induced CCL2 secretion without affecting CCL2 mRNA or protein expression. Co-incubation with geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, prevented the effect of simvastatin. By comparison, inhibiting protein isoprenylation with GGTI-298, but not FTI-277, mimicked the effect of simvastatin and significantly attenuated transendothelial migration in vitro. Inhibition of the monomeric GTPase Cdc42, but not Rac1 or RhoA-C, attenuated TNF-α mediated CCL2 secretion. TNF-α mediated trafficking of autoreactive leukocytes into peripheral nerves during GBS may proceed by a mechanism that involves Cdc42 facilitated secretion of CCL2.
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