PT - JOURNAL ARTICLE AU - Hanan S. M. Farghaly AU - Ian S. Blagbrough AU - David A. Medina-Tato AU - Malcolm L. Watson TI - Interleukin 13 Increases Contractility of Murine Tracheal Smooth Muscle by a Phosphoinositide 3-kinase p110δ-Dependent Mechanism AID - 10.1124/mol.108.045419 DP - 2008 May 01 TA - Molecular Pharmacology PG - 1530--1537 VI - 73 IP - 5 4099 - http://molpharm.aspetjournals.org/content/73/5/1530.short 4100 - http://molpharm.aspetjournals.org/content/73/5/1530.full SO - Mol Pharmacol2008 May 01; 73 AB - 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 p110δ 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 (Emax) 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 p110δ 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 p110δ in IL-13-induced hyper-responsiveness, IL-13 was unable to induce hyper-responsiveness in tissues from mice expressing the catalytically inactive form of p110δ (p110δD910A). These data indicate that IL-13 contributes to tracheal smooth muscle hyper-responsiveness via the PI3K p110δ isoform. In addition to previously reported effects on airway inflammation, inhibition of PI3K p110δ may be a useful target for the treatment of asthma by preventing IL-13-induced airway smooth muscle hyper-responsiveness.