Farghaly Hanan S M, Blagbrough Ian S, Medina-Tato David A, Watson Malcolm L
Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.
Mol Pharmacol. 2008 May;73(5):1530-7. doi: 10.1124/mol.108.045419. Epub 2008 Feb 14.
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 p110delta 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 p110delta 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 p110delta in IL-13-induced hyper-responsiveness, IL-13 was unable to induce hyper-responsiveness in tissues from mice expressing the catalytically inactive form of p110delta (p110delta(D910A)). These data indicate that IL-13 contributes to tracheal smooth muscle hyper-responsiveness via the PI3K p110delta isoform. In addition to previously reported effects on airway inflammation, inhibition of PI3K p110delta may be a useful target for the treatment of asthma by preventing IL-13-induced airway smooth muscle hyper-responsiveness.
Th2细胞因子白细胞介素（IL）-13可引发一系列反应，这与它在哮喘发病机制中起关键作用相一致。我们运用药理学和遗传学方法，来证明I类磷酸肌醇3激酶p110δ亚型信号传导在体外IL-13诱导的小鼠气管平滑肌收缩反应性增强中的作用。通过Akt磷酸化评估，IL-13处理气管组织与磷酸肌醇3激酶（PI3K）的早期激活有关。气管平滑肌收缩性经IL-13过夜孵育后增强，导致对卡巴胆碱（CCh）和氯化钾（KCl）的最大收缩反应（E(max)）增加。用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（LY294002），或PI3K p110δ亚型选择性抑制剂2-（6-氨基嘌呤-9-基甲基）-5-甲基-3-O-甲苯基-3H-喹唑啉-4-酮（IC87114）抑制PI3K，可防止IL-13诱导的反应性增强。与PI3K p110δ在IL-13诱导的反应性增强中发挥作用一致，IL-13无法在表达催化失活形式p110δ（p110δ(D910A)）的小鼠组织中诱导反应性增强。这些数据表明，IL-13通过PI3K p110δ亚型导致气管平滑肌反应性增强。除了先前报道的对气道炎症的影响外，抑制PI3K p110δ可能是通过防止IL-13诱导的气道平滑肌反应性增强来治疗哮喘的一个有用靶点。
