Promoting effects of IL-13 on Ca 2+ release and store-operated Ca 2+ entry in airway smooth muscle cells

Abstract

Th2 cytokine interleukin (IL)-13 plays a central role in the pathogenesis of allergic asthma. IL-13 exhibits a direct effect on airway smooth muscle cells (ASMCs) to cause airway hyperresponsiveness. IL-13 has been demonstrated to regulate Ca 2+ signaling in ASMCs, but the underlying mechanisms are not fully understood. Store-operated Ca 2+ entry (SOCE) plays an important role in regulating Ca 2+ signaling and cellular responses of ASMCs, whether IL-13 affects SOCE in ASMCs has not been reported. In this study, by using confocal Ca 2+ fluorescence imaging, we found that IL-13 (10 ng/ml) treatment increased basal intracellular Ca 2+ ([Ca 2+] i) level, Ca 2+ release and SOCE induced by SERCA inhibitor thapsigargin in rat bronchial smooth muscle cells. The glucocorticoid dexamethasone and the short-acting β2 adrenergic agonist (β2 agonist) salbutamol suppressed IL-13-augumented basal [Ca 2+] i, Ca 2+ release and SOCE, whereas the long-acting β2 agonist salmeterol had no effect on altered Ca 2+ signaling in IL-13-treated ASMCs. Membrane-permeable cAMP analog dibutyryl-cAMP (db-cAMP) similarly decreased Ca 2+ release and SOCE induced by thapsigargin in IL-13-treated ASMCs, confirmed a role of cAMP/PKA signaling pathway in the regulation of SOCE. IL-13 promoted the proliferation of ASMCs stimulated by serum; this effect was inhibited by nonspecific Ca 2+ channel blockers SKF-96365 and NiCl 2, by salmeterol, but not by salbutamol and dexamethasone. IL-13 treatment did not change the expression of SOC channel-associated molecules STIM1, Orai1 and TRPC1 at mRNA level. Our findings identified a promoting effect of IL-13 on Ca 2+ release and SOCE in ASMCs, which partially contributes to its effect on the proliferation of ASMCs; the differences of glucocorticoids and β2 agonists in inhibiting Ca 2+ signal and proliferation potentiated by IL-13 suggest that these therapies of asthma may have distinct effect on the relief of airway contraction and remodeling in bronchial asthma.