Interleukin 13 increases contractility of murine tracheal smooth muscle by a phosphoinositide 3-kinase p110delta-dependent mechanism.
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.
Farghaly
Hanan S M
HS
Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.
Blagbrough
Ian S
IS
Medina-Tato
David A
DA
Watson
Malcolm L
ML
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000201:enzymology; D002217:Carbachol / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases; D066298:In Vitro Techniques; D018793:Interleukin-13 / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008817:Mice, Mutant Strains; D009025:Morpholines / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology*; D050505:Mutant Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D014020:Tissue Extracts; D014132:Trachea / Q000187:drug effects* / Q000201:enzymology*
D000225:Adenine; D002217:Carbachol; D002867:Chromones; D058534:Class I Phosphatidylinositol 3-Kinases; D018793:Interleukin-13; D007527:Isoenzymes; D009025:Morpholines; D050505:Mutant Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011189:Potassium Chloride; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D014020:Tissue Extracts; C477872:IC 87114; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse