Interleukin 13 increases contractility of murine tracheal smooth muscle by a phosphoinositide 3-kinase p110δ-dependent mechanism

H S M Farghaly, I S Blagbrough, D A Medina-Tato, Malcolm L Watson

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31 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1530-1537
Number of pages8
JournalMolecular Pharmacology
Volume73
Issue number5
Early online date14 Feb 2008
DOIs
Publication statusPublished - May 2008

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