MAP kinases mediate interleukin-13 effects on calcium signaling in human airway smooth muscle cells

1 Meakins-Christie Laboratories, Department of Medicine, McGill University; and 2 Notre Dame Hospital, Universite de Montreal, Montreal, Canada Submitted 1 November 2007 ; accepted in final form 21 April 2008 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ responses to histamine. The augmentation of Ca 2+ 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 the IL-13-induced increase in histamine receptors. We conclude that IL-13 induces potentiation of Ca 2+ responses to contractile agonists by affecting mechanisms downstream of receptors. JNK and ERK MAPKs modulate these mechanisms. lung; allergy; inflammation; cytokines; mitogen-activated protein kinase Address for reprint requests and other correspondence: J. G. Martin, Meakins-Christie Laboratories, Dept. of Medicine, McGill Univ., 3626 St. Urbain, Montreal, Quebec, H2X 2P2 Canada (e-mail: james.martin{at}mcgill.ca )