Jordan University of Science and Technology

Epinephrine Activation of the B2-Adrenoceptor Is Required for IL-13-Induced Mucin Production in Human Bronchial Epithelial Cells.


Authors:  Al-Sawalha N, Pokkunuri I, Omoluabi O, Kim H, Thanawala VJ, Hernandez A, Bond RA, Knoll BJ

Abstract:  
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 ?2-adrenoceptor (?2AR) agonists, which are effective acutely as bronchodilators, however chronic use may lead to a worsening of asthma symptoms. In this study, we asked whether ?2AR 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 ?2AR antagonist, but not by CGP-20712A, a preferential ?1AR antagonist. Constitutive ?2AR activity was not sufficient for IL-13 induced mucin production and ?-agonist-induced signaling is required. A clinically important long-acting ?-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 ?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 ?2AR-agonists may contribute to asthma exacerbations by increasing mucin production via activation of ?2ARs on epithelial cells.