Epinephrine Activation of the β2-Adrenoceptor Is Required for IL-13-Induced Mucin Production in Human Bronchial Epithelial Cells

• Published in: PloS one Vol. 10; no. 7; p. e0132559
• Main Authors: Al-Sawalha, Nour, Pokkunuri, Indira, Omoluabi, Ozozoma, Kim, Hosu, Thanawala, Vaidehi J, Hernandez, Adrian, Bond, Richard A, Knoll, Brian J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.07.2015; Public Library of Science (PLoS)
• Subjects: Activation; Adenosine; Adrenergic beta-2 Receptor Agonists - pharmacology; Adrenergic receptors; Animals; Apoptosis; Asthma; Binding sites; Biochemistry; Biology; Bronchi - cytology; Bronchodilators; Cattle; Chronic illnesses; Cyclic AMP; Cyclic AMP - pharmacology; Cyclic AMP-Dependent Protein Kinases - metabolism; Epinephrine; Epinephrine - pharmacology; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - enzymology; Epithelial Cells - metabolism; Epithelium; Extracellular signal-regulated kinase; Formoterol; Forskolin; Humans; Inflammation; Interleukin 13; Interleukin-13 - pharmacology; JNK protein; Kinases; Lymphocytes T; MAP Kinase Signaling System - drug effects; Mucin; Mucin 5AC - metabolism; Mucus; Pathogenesis; Pharmaceutical sciences; Pharmacy; Physiology; Receptors, Adrenergic, beta-2 - metabolism; Respiratory tract; Rodents; Signaling; Transcription
• 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 TH2 cytokine, IL-13 is sufficient to cause mucus hypersecretion in vivo and in vitro. Asthma therapy often utilizes β2-adrenoceptor (β2AR) agonists, which are effective acutely as bronchodilators, however chronic use may lead to a worsening of asthma symptoms. In this study, we asked whether β2AR 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 β2AR antagonist, but not by CGP-20712A, a preferential β1AR antagonist. Constitutive β2AR activity was not sufficient for IL-13 induced mucin production and β-agonist-induced signaling is required. A clinically important long-acting β-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 β2AR 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 β2AR-agonists may contribute to asthma exacerbations by increasing mucin production via activation of β2ARs on epithelial cells.