Promoting effects of IL-13 on Ca2+ release and store-operated Ca2+ entry in airway smooth muscle cells.
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 beta2 adrenergic agonist (beta2 agonist) salbutamol suppressed IL-13-augumented basal [Ca(2+)](i), Ca(2+) release and SOCE, whereas the long-acting beta2 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 beta2 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.
Gao
Ya-dong
YD
Department of Respiratory Medicine, Zhongnan Hospital, Wuhan University, Wuhan 430071, PR China.
Zou
Jin-jing
JJ
Zheng
Jun-wen
JW
Shang
Min
M
Chen
Xia
X
Geng
Shuang
S
Yang
Jiong
J
D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001993:Bronchodilator Agents / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D066298:In Vitro Techniques; D018793:Interleukin-13 / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D019284:Thapsigargin / Q000494:pharmacology
D001993:Bronchodilator Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018793:Interleukin-13; D003994:Bucladesine; D019284:Thapsigargin; D003907:Dexamethasone; D000420:Albuterol; D002118:Calcium