MAP kinases mediate interleukin-13 effects on calcium signaling in human airway smooth muscle cells.
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.
Moynihan
Barry
B
Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
Tolloczko
Barbara
B
Michoud
Marie-Claire
MC
Tamaoka
Meiyo
M
Ferraro
Pasquale
P
Martin
James G
JG
D001249:Asthma / Q000378:metabolism; D016085:Bronchoconstrictor Agents / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006632:Histamine / Q000378:metabolism; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D053660:Receptors, Interleukin-13 / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism
D016085:Bronchoconstrictor Agents; D018793:Interleukin-13; D053660:Receptors, Interleukin-13; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D006632:Histamine; D048049:Extracellular Signal-Regulated MAP Kinases