Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation
Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation
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DOI：
10.1152/ajpcell.00160.2009
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发表时间：
2009-11-01
影响因子：
5.5
通讯作者：
Metz, Christine N.
中科院分区：
文献类型：
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作者：
Chatterjee, Prodyot K.;Al-Abed, Yousef;Metz, Christine N.
Chatterjee PK，Al-Abed Y，Sherry B，梅斯CN.胆碱能激动剂调节JAK 2/STAT 3信号传导以抑制内皮细胞活化。美国生理学杂志细胞生理学297：C1294-C1306，2009年。首次发表于2009年9月9日; doi：10.1152/ajpcell.00160.2009。胆碱能抗炎途径是一种生理机制，抑制细胞因子的产生，并最大限度地减少炎症过程中的组织损伤。以前的研究表明，胆碱能刺激（通过胆碱能激动剂和迷走神经刺激）抑制内皮细胞活化和白细胞募集。本研究的目的是探讨胆碱能受体激动剂（e。例如，在一个实施例中，尼古丁和GTS-21）调节内皮细胞活化。具体而言，我们研究了胆碱能激动剂对IL-6介导的内皮细胞活化通过JAK 2/STAT 3信号通路的影响。用胆碱能激动剂尼古丁和GTS-21处理大血管人脐静脉内皮细胞（HUVEC）和微血管内皮细胞（MVEC）可显着减少IL-6介导的单核细胞趋化蛋白-1（MCP-1）的产生和ICAM-1的表达，这些都是通过JAK 2/STAT 3途径调节的。我们发现用胆碱能激动剂处理内皮细胞显著降低了STAT 3通过磷酸化和DNA结合的活化。STAT 3磷酸化的抑制被酪氨酸磷酸酶抑制剂原钒酸钠以及NSC-87877逆转，表明SHP 1/2依赖性机制。进一步的研究表明，胆碱能激动剂减少JAK 2的磷酸化，JAK 2/STAT 3通路的上游组分。最后，我们观察到尼古丁和GTS-21处理降低了活化内皮细胞中SOCS 3（细胞因子信号传导抑制因子; IL-6炎症活性调节因子）的水平。这些数据表明胆碱能激动剂通过JAK 2/STAT 3途径抑制IL-6介导的内皮细胞活化。我们的研究结果对于更好地理解胆碱能激动剂治疗IL-6介导的炎症性疾病的治疗潜力具有重要意义。
Chatterjee PK, Al-Abed Y, Sherry B, Metz CN. Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation. Am J Physiol Cell Physiol 297: C1294-C1306, 2009. First published September 9, 2009; doi:10.1152/ajpcell.00160.2009.-The cholinergic anti-inflammatory pathway is a physiological mechanism that inhibits cytokine production and minimizes tissue injury during inflammation. Previous investigations revealed that cholinergic stimulation (via cholinergic agonists and vagus nerve stimulation) suppresses endothelial cell activation and leukocyte recruitment. The purpose of this study was to investigate the mechanisms by which cholinergic agonists (e. g., nicotine and GTS-21) regulate endothelial cell activation. Specifically, we examined the effects of cholinergic agonists on IL-6-mediated endothelial cell activation through the JAK2/STAT3 signaling pathway. Treatment of macrovascular human umbilical vein endothelial cells (HUVECs) and microvascular endothelial cells (MVECs) with the cholinergic agonists nicotine and GTS-21 significantly reduced IL-6-mediated monocyte chemoattractant protein-1 (MCP-1) production and ICAM-1 expression which are regulated through the JAK2/STAT3 pathway. We found that treatment of endothelial cells with cholinergic agonists significantly reduced STAT3 activation by phosphorylation and DNA binding. The inhibition of STAT3 phosphorylation was reversed by sodium orthovanadate, an inhibitor of tyrosine phosphatases, as well as by NSC-87877 suggesting a SHP1/2-dependent mechanism. Further investigations showed that cholinergic agonists reduced the phosphorylation of JAK2, an upstream component of the JAK2/STAT3 pathway. Finally, we observed that nicotine and GTS-21 treatment decreased levels of SOCS3 (suppressor of cytokine signaling; a regulator of the inflammatory activity of IL-6) in activated endothelial cells. These data demonstrate that cholinergic agonists suppress IL-6-mediated endothelial cell activation through the JAK2/STAT3 pathway. Our results have significant implications for better understanding the therapeutic potential of cholinergic agonists for treating IL-6 mediated inflammatory conditions.