Calcium-Calmodulin Mediates House Dust Mite-Induced ERK Activation and IL-8 Production in Human Respiratory Epithelial Cells

BACKGROUND: House dust mites (HDM) have been shown to be important sources of indoor allergens associated with asthma and other allergic conditions. While exogenous proteases from allergens have a direct proinflammatory role in the respiratory tract, the precise mechanisms underlying the release of cytokines from the respiratory epithelium are unclear. OBJECTIVES: The present study examines that extracellular signal-regulated kinase (ERK) activated downstream of the Ca(2+)-sensitive tyrosine kinase plays an important role in the efficient activation of the HDM-induced IL-8 signaling pathway. METHODS: We examined the effect of HDM, and the role of the Ca(2+)/calmodulin system and mitogen-activated protein kinases, on IL-8 expression in human lung epithelial cells. RESULTS: In H292 cells, HDM induced IL-8 release in a time- and/or dose-dependent manner. This IL-8 release was abolished by treatment with intracellular Ca(2+) chelator (BAPTA-AM), but not by EGTA or nifedipine. Calmodulin inhibitor (calmidazolium) and tyrosine kinase inhibitor (genistein) almost completely blocked IL-8 release by HDM. PD98,059, an ERK pathway inhibitor, completely abolished HDM-induced IL-8 release. Moreover, PD98,059, BAPTA-AM, calmidazolium and genistein suppressed the HDM-induced ERK phosphorylation. CONCLUSIONS: HDM-induced IL-8 production is predominantly regulated by Ca(2+)/calmodulin signaling, and ERK plays an important role in signal transmission for efficient activation of the HDM-induced IL-8 signaling pathway.ope