title: Epinephrine Activation of the β2-Adrenoceptor Is Required for IL-13-Induced Mucin Production in Human Bronchial Epithelial Cells.
abstract: 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.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 4800 Calhoun Road, Houston, Texas, 77204, United States of America.
authors.forename: Nour
authors.initials: N
authors.lastname: Al-Sawalha
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 4800 Calhoun Road, Houston, Texas, 77204, United States of America.
authors.forename: Indira
authors.initials: I
authors.lastname: Pokkunuri
authors.affiliation: Department of Biology and Biochemistry, University of Houston, 4800 Calhoun Road, Houston, Texas, 77204, United States of America.
authors.forename: Ozozoma
authors.initials: O
authors.lastname: Omoluabi
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 4800 Calhoun Road, Houston, Texas, 77204, United States of America.
authors.forename: Hosu
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 4800 Calhoun Road, Houston, Texas, 77204, United States of America.
authors.forename: Vaidehi J
authors.initials: VJ
authors.lastname: Thanawala
authors.affiliation: Department of Biology and Biochemistry, University of Houston, 4800 Calhoun Road, Houston, Texas, 77204, United States of America.
authors.forename: Adrian
authors.initials: A
authors.lastname: Hernandez
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 4800 Calhoun Road, Houston, Texas, 77204, United States of America; Department of Biology and Biochemistry, University of Houston, 4800 Calhoun Road, Houston, Texas, 77204, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bond
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 4800 Calhoun Road, Houston, Texas, 77204, United States of America; Department of Biology and Biochemistry, University of Houston, 4800 Calhoun Road, Houston, Texas, 77204, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Knoll
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000166:cytology*; D002417:Cattle; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D055271:Mucin 5AC / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018793:Interleukin-13; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D018343:Receptors, Adrenergic, beta-2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004837:Epinephrine