Counterregulation of [beta]2-adrenoceptor function in human mast cells by stem cell factor

• Published in: Journal of allergy and clinical immunology Vol. 125; no. 1; p. 257
• Main Authors: Cruse, Glenn, Yang, Weidong, Duffy, S Mark, Chachi, Latifah, Leyland, Mark, Amrani, Yassine, Bradding, Peter
• Format: Journal Article
• Language: English
• Published: St. Louis Elsevier Limited 01.01.2010
• Subjects: Biotechnology; Flow cytometry; Haplotypes; Microscopy; Phosphorylation; Smooth muscle; Software; Statistical analysis; Studies; United Kingdom > UK
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2009.08.020

Background Mast cells contribute to the pathophysiology of asthma with the sustained release of both preformed and newly generated mediators in response to allergens and other diverse stimuli. Stem cell factor (SCF) is the key human mast cell growth factor, but also primes mast cells for mediator release. SCF expression is markedly increased in asthmatic airways. Short-acting β2-adrenoceptor drugs such as albuterol inhibit human lung mast cell (HLMC) degranulationin vitroin the absence of SCF, but their effect in the presence of SCF is not known. Objective The aim of this study was to elucidate the effects of albuterol on HLMC function in the presence of SCF. Methods Mediator release and KCa3.1 ion channel activity were analyzed in purified HLMC. Intracellular signalling and β2-adrenoceptor phosphorylation and internalization were analyzed in the HMC-1 human mast cell line. Results β2-Adrenoceptor agonist-dependent inhibition of KCa3.1 ion channels and HLMC mediator release was markedly attenuated in the presence of SCF. Remarkably, albuterol actually potentiated IgE-induced histamine release in a dose-dependent manner when both SCF and IgE were present. These effects were related to the SCF-dependent phosphorylation of Tyr350 on the β2-adrenoceptor with immediate uncoupling of the receptor followed by receptor internalization. Conclusion The potentially beneficial effects of β2-adrenoceptor agonists in asthmatic airways may be blunted as a result of the high concentrations of SCF present.