Activation of β2-Adrenoceptors Is Required for Mucin Production in Airway Bronchial Epithelial Cells
Al-Sawalha, Nour A
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Asthma, a chronic inflammatory disease of the airways, is associated with mucus hypersecretion by airway epithelium. Accumulated mucus in the airways contributes to airway obstruction, airway hyperresponsiveness and sometimes death. In a murine model of asthma, chronically blocking β2-adrenoceptors (β2-ARs) or genetic ablation of β2-ARs causes a reduction in mucus secretion, an index of inflammatory responses, in response to allergen. The detailed molecular components of these effects remain to be elucidated. We examined the β2-AR signaling pathways involved in mediating mucin production in response to IL-13 in airway epithelial cells. The expression of MUC5AC, the predominant mucin-producing gene in asthma, and mucin content were induced by IL-13 in normal human bronchial epithelial (NHBE) cells as compared to control cells only in the presence of epinephrine. Blocking β2-ARs, but not β1-ARs, attenuated the IL-13 effect. The three members of MAPK family, ERK1/2, p38 and JNK, were all involved in inducing mucin production in response to IL-13 in the presence of epinephrine. Since β2-ARs signal through the canonical Gs-adenylyl cyclase or β-arrestin signaling cascade, we examined each pathway separately. Elevating intracellular cAMP levels was associated with enhanced IL-13 response, either in the presence or absence of epinephrine and increased epithelial cell number. Moreover, inhibiting the activity of PKA and PDE4 resulted in attenuated IL-13 response. Stimulating β-arrestin-2 signaling did not alter the IL-13 response in NHBE cells, either in the presence or absence of epinephrine. However, the absence of β-arrestin-2 from mouse airway epithelial cells attenuated the response to IL-13 as compared to cells expressing β-arrestin-2. β2-ARs did not seem to affect IL-13 mediated mucuciliary shift from ciliated to goblet cells or cell proliferation. We conclude that, in human bronchial epithelial cells, epinephrine-induced β2-AR signaling is required to enhance mucus production in response to IL-13. Moreover, MAPKs, cAMP and cAMPdependent protein kinases are all involved components of β2-AR signaling in mediating the effect of IL-13 in NHBE cells.