Submitted on November 1, 2007
Accepted on April 21, 2008
MAP kinases mediate interleukin-13 effects on calcium signaling in human airway smooth muscle cells
Barry Moynihan1, Barbara Tolloczko1, Marie-Claire Michoud1, Meiyo Tamaoka1, Pasquale Ferraro2, and James G. Martin1*
1 Department of Medicine, Meakins-Christie Laboratories, McGill University, Montreal, Canada
2 Notre Dame Hospital, Universite de Montreal, Montreal, Canada
* To whom correspondence should be addressed. E-mail: james.martin{at}mcgill.ca.
Interleukin-13 (IL-13) has been strongly implicated in the pathogenesis of allergic asthma through animal models that have shown that IL-13 is both necessary and sufficient to cause airway hyperresponsiveness (AHR). Airway smooth muscle (ASM) is a primary effector of AHR and IL-13 increases the responsiveness of ASM, by increasing calcium (Ca2+) release intracellularly, to bronchoconstrictors such as histamine. The mechanisms and signaling pathways mediating this effect are incompletely understood. We have investigated the pathways through which IL-13 regulates the Ca2+ response to histamine in primary human ASM cell cultures. Functional IL-13 receptors were demonstrated by IL-13 mediated phosphorylation of signal transducer and activator of transcription 6 (STAT6) and mitogen activated protein kinases (MAPKs). IL-13 increased Ca2+ responses to histamine. The augmentation of Ca2+ signaling was not affected by inhibition of STAT6, or p38 MAPK signaling but was prevented by concurrent inhibition of c-jun N-terminal kinase (JNK) and extracellular signal related kinase (ERK) MAPKs. This inhibition did not affect IL-13-induced increase in histamine receptors. We conclude that IL-13 induces potentiation of Ca2+ responses to contractile agonists by affecting mechanisms downstream of receptors. JNK and ERK MAPKs modulate these mechanisms.
