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

Abstract

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 Ca²⁺-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 Ca²⁺/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 Ca²⁺ 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. PD98059, an ERK pathway inhibitor, completely abolished HDM-induced IL-8 release. Moreover, PD98059, BAPTA-AM, calmidazolium and genistein suppressed the HDM-induced ERK phosphorylation. Conclusions: HDM-induced IL-8 production is predominantly regulated by Ca²⁺/calmodulin signaling, and ERK plays an important role in signal transmission for efficient activation of the HDM-induced IL-8 signaling pathway.