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

摘要

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+)]j) level, Ca~(2+) release and SOCE induced by SERCA inhibitor thapsigargin in rat r bronchial smooth muscle cells. The glucocorticoid dexamethasone and the short-acting fS2 adrenergic agonist (32 agonist) salbutamol suppressed IL-13-augumented basal [Ca~(2+)]j, Ca~(2+) release and SOCE, whereas the long-acting |32 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 NiCb, by salmeterol, but not by salbutamol and dexamethasone. IL-13 treatment did not change the expression of SOC channel-associated molecules STIM1, Orail 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 {32 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.