Up-regulation of airway smooth muscle histamine H1 receptor mRNA, protein, and function by β2-adrenoceptor activation

Abstract

Histamine, released from activated mast cells, causes bronchoconstriction mediated by H1 receptors, whereas β2-agonists are widely used for the relief of bronchoconstriction. In this study, we examined the effects of the β2-adrenoceptor agonist, fenoterol, on the expression of H1 receptors at the mRNA and protein levels, and functional responses, incubation of bovine tracheal smooth muscle with fenoterol (10-7 M) for 2 h increased H1 receptor mRNA (maximum ~190%). The number of H1 receptors was increased after 12 and 18 h without any change in binding affinity. In the contraction experiments, the concentration-response curves for histamine- induced contraction were shifted significantly to the left after 18-h exposure to fenoterol, consistent with the increase in receptor number. The fenoterol-induced increase in H1 receptor mRNA was concentration-dependent and was abolished by propranolol and ICI 118551, but not by CGP 20712A, indicating that fenoterol acts via β2-adrenoceptors. These effects were mimicked by other cAMP-elevating agents forskolin and prostaglandin E2, and by the stable cAMP analog 8-bromo-cAMP. Cycloheximide alone produced superinduction of H1 receptor mRNA and augmented the fenoterol-induced increase in H1 receptor mRNA. Fenoterol increased both the stability and the transcription rate of H1 receptor mRNA. Pretreatment with dexamethasone did not prevent fenoterol-induced up-regulation of H1 receptor mRNA. Thus, fenoterol increases the expression of airway smooth muscle H1 receptors via activation of the cAMP system through increased gene transcription and mRNA stability. This mechanism may be involved in the adverse responses encountered with the clinical use of short-acting β2-agonists.