Counterregulation of beta(2)-adrenoceptor function in human mast cells by stem cell factor.
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 beta(2)-adrenoceptor drugs such as albuterol inhibit human lung mast cell (HLMC) degranulation in vitro in 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 K(Ca)3.1 ion channel activity were analyzed in purified HLMC. Intracellular signalling and beta(2)-adrenoceptor phosphorylation and internalization were analyzed in the HMC-1 human mast cell line.


RESULTS
beta(2)-Adrenoceptor agonist-dependent inhibition of K(Ca)3.1 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 beta(2)-adrenoceptor with immediate uncoupling of the receptor followed by receptor internalization.


CONCLUSIONS
The potentially beneficial effects of beta(2)-adrenoceptor agonists in asthmatic airways may be blunted as a result of the high concentrations of SCF present.
Cruse
Glenn
G
Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom. glenncruse@hotmail.com
Yang
Weidong
W
Duffy
S Mark
SM
Chachi
Latifah
L
Leyland
Mark
M
Amrani
Yassine
Y
Bradding
Peter
P
D000420:Albuterol / Q000378:metabolism / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D006636:Histamine Release; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology*
D024681:Potassium Channels, Calcium-Activated; D018343:Receptors, Adrenergic, beta-2; D019089:Stem Cell Factor; D000420:Albuterol