Interleukin-17A directly acts on bronchial smooth muscle cells and augments the contractility
Interleukin-17A directly acts on bronchial smooth muscle cells and augments the contractility
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DOI：
10.1016/j.pharep.2016.12.007
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发表时间：
2017-06-01
影响因子：
4.4
通讯作者：
Saka, Hiroyasu
中科院分区：
文献类型：
--
作者：
Chiba, Yoshihiko;Tanoue, Gen;Saka, Hiroyasu
背景：虽然白细胞介素-17 （IL-17）有助于哮喘气道高反应性的诱导，但其对支气管平滑肌（BSM）的影响仍不清楚。有证据支持RhoA/ rho激酶参与BSM收缩，并且该途径现已被提出作为哮喘治疗的新靶点。为了阐明IL-17在BSM高反应性发展中的作用，我们研究了IL-17A对BSM收缩性和RhoA表达的影响。方法：采用雄性BALB/c小鼠和培养的人BSM细胞（hBSMCs）。结果：在小鼠变应性哮喘模型中，观察到BSM高反应性，支气管肺泡灌洗液中IL-17A上调。RT-PCR分析显示IL-17A受体在小鼠bsm和hBSMCs中表达。在hBSMCs中，IL-17A孵育引起rhoa蛋白的上调。Western blot分析还发现，IL-17A处理的hBSMCs中JNKs/ERKs磷酸化，l κ pa b - α下调，表明IL-17A可以直接作用于BSM细胞。然而，IL- 17A没有激活STAT6， STAT6也是一种被IL-13激活时导致RhoA上调的信号分子。另一方面，IL-17A导致miR-133a-3p的下调，miR-133a-3p是一种负向调控RhoA翻译的microRNA。在幼年小鼠中，经鼻内滴入IL-17A治疗气道诱导BSM高反应性，RhoA蛋白上调。结论：这些发现表明IL-17直接作用于BSM细胞，可能通过下调miR-133a-3p上调RhoA蛋白，从而诱导BSM超反应性。(C) 2016年由Elsevier Sp. z . o.o.代表波兰科学院药理学研究所出版。
Background: Although interleukin-17 (IL-17) contributes to the induction of airway hyperresponsiveness in asthma, its effect on bronchial smooth muscle (BSM) remains largely unknown. Evidence support an involvement of RhoA/Rho-kinase in BSM contraction, and the pathway has now been proposed as a novel target for asthma therapy. To clarify the role of IL-17 on the development of BSM hyperresponsiveness, effects of IL-17A on BSM contractility and RhoA expression were investigated.Methods: Male BALB/c mice and cultured human BSM cells (hBSMCs) were used.Results: In the murine model of allergic asthma, BSM hyperresponsiveness with an IL-17A up-regulation in bronchoalveolar lavage fluids were observed. RT-PCR analyses revealed the expression of receptors for IL-17A in mouse BSMs and hBSMCs. In the hBSMCs, incubation with IL-17A caused an up-regulation of RhoAprotein. Western blot analyses also revealed phosphorylations of JNKs/ERKs and a down-regulation of l kappa B-alpha in the IL-17A-treated hBSMCs, indicating that IL-17A could acton BSM cells directly. However, IL- 17A did not activate STAT6, which is also known as a signaling molecule that causes an up-regulation of RhoA when activated by IL-13. On the other hand, IL-17A caused a down-regulation of miR-133a-3p, a microRNA that negatively regulates RhoA translation. In the naive mice, in vivo IL-17A treatment to the airways by intranasal instillation induced a BSM hyperresponsiveness with RhoA protein up-regulation.Conclusions: These findings indicate that IL-17 directly acts on BSM cells and up-regulates RhoA protein probably via a down-regulation of miR-133a-3p, resulting in an induction of the BSM hyper responsiveness. (C) 2016 Published by Elsevier Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.