Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation.
Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation.
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DOI：
10.1084/jem.20040463
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发表时间：
2005-04-04
期刊：
影响因子：
--
通讯作者：
Metz CN
中科院分区：
文献类型：
--
作者：
Saeed RW;Varma S;Peng-Nemeroff T;Sherry B;Balakhaneh D;Huston J;Tracey KJ;Al-Abed Y;Metz CN
内皮细胞活化在炎症和感染期间调节白细胞募集中起关键作用。基于最近的研究表明乙酰胆碱和其他胆碱能介质通过巨噬细胞表达的α7烟碱乙酰胆碱受体（α7 nAChR）抑制促炎细胞因子的产生，以及我们观察到人微血管内皮细胞表达α7 nAChR，我们在体外和体内研究了胆碱能刺激对内皮细胞活化的影响。使用Shwartzman反应，我们观察到尼古丁（2 mg/kg）和新型胆碱能药物CAP 55（12 mg/kg）抑制内皮细胞粘附分子表达。使用内皮细胞培养，我们观察了乙酰胆碱和胆碱能药物对肿瘤坏死因子（TNF）诱导的内皮细胞活化的直接抑制作用。nAChR拮抗剂美加明逆转了两种胆碱能激动剂对内皮细胞活化的抑制作用，证实了nAChR胆碱能通路的抑制作用。体外机制研究表明，尼古丁以抑制剂κB（IκB）α和IκB α依赖性方式阻断TNF诱导的核因子-κB核进入。最后，在角叉菜胶气囊模型中，迷走神经刺激和胆碱能激动剂均显著阻断体内白细胞迁移。这些发现确定了内皮细胞，炎症过程中白细胞运输的关键调节因子，作为抗炎胆碱能介质的靶点。
Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Based on recent studies showing that acetylcholine and other cholinergic mediators suppress the production of proinflammatory cytokines via the α7 nicotinic acetylcholine receptor (α7 nAChR) expressed by macrophages and our observations that human microvascular endothelial cells express the α7 nAChR, we examined the effect of cholinergic stimulation on endothelial cell activation in vitro and in vivo. Using the Shwartzman reaction, we observed that nicotine (2 mg/kg) and the novel cholinergic agent CAP55 (12 mg/kg) inhibit endothelial cell adhesion molecule expression. Using endothelial cell cultures, we observed the direct inhibitory effects of acetylcholine and cholinergic agents on tumor necrosis factor (TNF)-induced endothelial cell activation. Mecamylamine, an nAChR antagonist, reversed the inhibition of endothelial cell activation by both cholinergic agonists, confirming the antiinflammatory role of the nAChR cholinergic pathway. In vitro mechanistic studies revealed that nicotine blocked TNF-induced nuclear factor–κB nuclear entry in an inhibitor κB (IκB)α- and IκBɛ-dependent manner. Finally, with the carrageenan air pouch model, both vagus nerve stimulation and cholinergic agonists significantly blocked leukocyte migration in vivo. These findings identify the endothelium, a key regulator of leukocyte trafficking during inflammation, as a target of anti-inflammatory cholinergic mediators.
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