Epinephrine Activation of the [beta].sub.2-Adrenoceptor Is Required for IL-13-Induced Mucin Production in Human Bronchial Epithelial Cells

• Published in: PloS one 2015-07, Vol.10 (7)
• Main Authors: Al-Sawalha, Nour, Pokkunuri, Indira, Omoluabi, Ozozoma, Kim, Hosu, Thanawala, Vaidehi J, Hernandez, Adrian, Bond, Richard A, Knoll, Brian J
• Format: Article
• Language: English
• Subjects: Asthma; Cytokines; Epinephrine; Mucins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0132559

Mucus hypersecretion by airway epithelium is a hallmark of inflammation in allergic asthma and results in airway narrowing and obstruction. Others have shown that administration a T.sub.H 2 cytokine, IL-13 is sufficient to cause mucus hypersecretion in vivo and in vitro. Asthma therapy often utilizes [beta].sub.2 -adrenoceptor ([beta].sub.2 AR) agonists, which are effective acutely as bronchodilators, however chronic use may lead to a worsening of asthma symptoms. In this study, we asked whether [beta].sub.2 AR signaling in normal human airway epithelial (NHBE) cells affected mucin production in response to IL-13. This cytokine markedly increased mucin production, but only in the presence of epinephrine. Mucin production was blocked by ICI-118,551, a preferential [beta].sub.2 AR antagonist, but not by CGP-20712A, a preferential [beta].sub.1 AR antagonist. Constitutive [beta].sub.2 AR activity was not sufficient for IL-13 induced mucin production and [beta]-agonist-induced signaling is required. A clinically important long-acting [beta]-agonist, formoterol, was as effective as epinephrine in potentiating IL-13 induced MUC5AC transcription. IL-13 induced mucin production in the presence of epinephrine was significantly reduced by treatment with selective inhibitors of ERK1/2 (FR180204), p38 (SB203580) and JNK (SP600125). Replacement of epinephrine with forskolin + IBMX resulted in a marked increase in mucin production in NHBE cells in response to IL-13, and treatment with the inhibitory cAMP analogue Rp-cAMPS decreased mucin levels induced by epinephrine + IL-13. Our findings suggest that [beta].sub.2 AR signaling is required for mucin production in response to IL-13, and that mitogen activated protein kinases and cAMP are necessary for this effect. These data lend support to the notion that [beta].sub.2 AR-agonists may contribute to asthma exacerbations by increasing mucin production via activation of [beta].sub.2 ARs on epithelial cells.