Received for publication January 17, 2008.
Revised February 12, 2008.
Accepted for publication February 13, 2008.

Interleukin 13 Increases Contractility of Murine Tracheal Smooth Muscle by a Phosphoinositide 3-kinase p110 Dependent Mechanism

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 utilised pharmacological and genetic approaches to demonstrate the role of signalling via the class I phosphoinositide 3-kinase p110 isoform in IL-13-induced hyperresponsiveness 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 LY294002, or the selective inhibitor of the PI3K p110 isoform IC87114, prevented IL-13-induced hyperresponsiveness. Consistent with a role for PI3K p110 in IL-13-induced hyperresponsiveness, IL-13 was unable to induce hyperresponsiveness in tissues from mice expressing the catalytically inactive form of p110 (p110^D910A). These data indicate that IL-13 contributes towards tracheal smooth muscle hyperresponsiveness via the PI3K p110 isoform. In addition to previously reported effects on airway inflammation, inhibition of PI3K p110 may be a useful target for the treatment of asthma by preventing IL 13-induced airway smooth muscle hyperresponsiveness.

Key words: Interleukins, Mutagenesis/Chimeric approaches