Substance P Activates Both Contractile and Inflammatory Pathways in Lymphatics Through the Neurokinin Receptors NK1R and NK3R
Substance P Activates Both Contractile and Inflammatory Pathways in Lymphatics Through the Neurokinin Receptors NK1R and NK3R
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DOI：
10.1111/j.1549-8719.2010.00064.x
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发表时间：
2011-01-01
期刊：
影响因子：
2.4
通讯作者：
Muthuchamy, Mariappan
中科院分区：
文献类型：
--
作者：
Chakraborty, Sanjukta;Nepiyushchikh, Zhanna;Muthuchamy, Mariappan
P>目的：本研究的目的是阐明 P 物质 (SP) 调节淋巴管收缩的分子信号传导机制，并确定 SP 是否刺激淋巴管中的收缩通路和炎症通路。方法：利用大鼠肠系膜淋巴肌细胞培养模型 (RMLMC) 和已知的特定药理学抑制剂来描绘 淋巴管中 SP 介导的信号通路。结果：我们检测到 RMLMC 中神经激肽受体 1 (NK1R) 和神经激肽受体 3 (NK3R) 的表达。 SP 刺激增加肌球蛋白轻链 20 (MLC20) 以及 p38 丝裂原相关蛋白激酶 (p38-MAPK) 和细胞外信号调节激酶 (ERK1/2) 的磷酸化，表明收缩和促炎 MAPK 途径均被激活。 NK1R 和 NK3R 的药理学抑制显着影响下游 SP 信号传导。我们进一步检查了 SP 刺激时两条通路之间是否存在任何串扰。 SP 激活后，抑制 ERK1/2 以 PKC 依赖性方式降低 p-MLC20 水平，表明这两种途径之间存在潜在的串扰。结论：这些数据提供了第一个证据，证明 SP 介导的促炎和收缩信号传导机制之间存在于淋巴系统中，并且可能是淋巴功能调节和炎症之间的重要桥梁。
P>Objective:The aim of this study was to elucidate the molecular signaling mechanisms by which substance P (SP) modulates lymphatic muscle contraction and to determine whether SP stimulates both contractile as well as inflammatory pathways in the lymphatics.Methods:A rat mesenteric lymphatic muscle cell culture model (RMLMCs) and known specific pharmacological inhibitors were utilized to delineate SP-mediated signaling pathways in lymphatics.Results:We detected expression of neurokinin receptor 1 (NK1R) and neurokinin receptor 3 (NK3R) in RMLMCs. SP stimulation increased phosphorylation of myosin light chain 20 (MLC20) as well as p38 mitogen associated protein kinase (p38-MAPK) and extracellular signal regulated kinase (ERK1/2) indicating activation of both a contractile and a pro-inflammatory MAPK pathway. Pharmacological inhibition of both NK1R and NK3R significantly affected the downstream SP signaling. We further examined whether there was any crosstalk between the two pathways upon SP stimulation. Inhibition of ERK1/2 decreased levels of p-MLC20 after SP activation, in a PKC dependent manner, indicating a potential crosstalk between these two pathways.Conclusions:These data provide the first evidence that SP-mediated crosstalk between pro-inflammatory and contractile signaling mechanisms exists in the lymphatic system and may be an important bridge between lymphatic function modulation and inflammation.