Epinephrine Activation Of The Beta(2)-Adrenoceptor Is Required For Il-13-Induced Mucin Production In Human Bronchial Epithelial Cells

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(H)2 cytokine, IL-13 is sufficient to cause mucus hypersecretion in vivo and in vitro. Asthma therapy often utilizes beta(2)-adrenoceptor (beta(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(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(2)AR antagonist, but not by CGP-20712A, a preferential beta 1AR antagonist. Constitutive beta(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 2AR 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 2AR-agonists may contribute to asthma exacerbations by increasing mucin production via activation of beta 2ARs on epithelial cells.