Interleukin 13 increases contractility of murine tracheal smooth muscle by a phosphoinositide 3-kinase p110δ-dependent mechanism
Interleukin 13 increases contractility of murine tracheal smooth muscle by a phosphoinositide 3-kinase p110δ-dependent mechanism
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DOI：
10.1124/mol.108.045419
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发表时间：
2008-05-01
影响因子：
3.6
通讯作者：
Watson, Malcolm L.
中科院分区：
文献类型：
--
作者：
Farghaly, Hanan S. M.;Blagbrough, Ian S.;Watson, Malcolm L.
Th 2细胞因子白细胞介素（IL）13可以引起许多反应，这与哮喘发病机制中的关键作用一致。我们已经使用药理学和遗传学的方法来证明通过I类磷脂酰肌醇3-激酶p110 δ亚型在IL-13诱导的小鼠气管平滑肌收缩高反应性中的作用。气管组织的IL-13治疗与磷酸肌醇3-激酶（PI 3 K）的早期活化相关，如通过Akt的磷酸化所评估的。气管平滑肌收缩性通过与IL-13过夜孵育而增强，导致对卡巴胆碱（CCh）和KCl的最大收缩（E-max）增加。通过非亚型选择性抑制剂渥曼青霉素或2-（4-吗啉基）-8-苯基-4H-1-苯并吡喃-4-酮（LY 294002）或PI 3 K p110 δ亚型2-（6-氨基嘌呤-9-基甲基）-5-甲基-3-O-甲苯基-3H-喹唑啉-4-酮（IC 87114）的选择性抑制剂抑制PI 3 K，可预防IL-13诱导的高反应性。与PI 3 K p110 δ在IL-13诱导的高反应性中的作用一致，IL-13不能在来自表达p110 δ（p110 δ（D910 A））的催化失活形式的小鼠的组织中诱导高反应性。这些数据表明，IL-13通过PI 3 K p110 δ亚型促进气管平滑肌高反应性。除了先前报道的对气道炎症的作用外，抑制PI 3 K p110 δ可能是通过预防IL-13诱导的气道平滑肌高反应性治疗哮喘的有用靶点。
The Th2 cytokine interleukin (IL) 13 can elicit a number of responses consistent with a key role in the pathogenesis of asthma. We have used pharmacological and genetic approaches to demonstrate the role of signaling via the class I phosphoinositide 3-kinase p110 delta isoform in IL-13-induced hyper-responsiveness of murine tracheal smooth muscle contractility in vitro. IL-13 treatment of tracheal tissue is associated with an early activation of phosphoinositide 3-kinase (PI3K), as assessed by phosphorylation of Akt. Tracheal smooth muscle contractility is enhanced by overnight incubation with IL-13, resulting in increased maximal contractions (E-max) to carbachol (CCh) and KCl. Inhibition of PI3K by the non-isoform-selective inhibitors wortmannin or 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), or the selective inhibitor of the PI3K p110 delta isoform 2-(6-aminopurin-9-ylmethyl)- 5-methyl-3-O-tolyl-3H-quinazolin-4-one (IC87114), prevented IL-13-induced hyper-responsiveness. Consistent with a role for PI3K p110 delta in IL-13-induced hyper-responsiveness, IL-13 was unable to induce hyper-responsiveness in tissues from mice expressing the catalytically inactive form of p110 delta (p110 delta(D910A)). These data indicate that IL-13 contributes to tracheal smooth muscle hyper-responsiveness via the PI3K p110 delta isoform. In addition to previously reported effects on airway inflammation, inhibition of PI3K p110 delta may be a useful target for the treatment of asthma by preventing IL-13-induced airway smooth muscle hyper-responsiveness.