Increased β2-adrenoceptor phosphorylation in airway smooth muscle in severe asthma: possible role of mast cell-derived growth factors.

The purpose of this study was to investigate whether growth factors produced by activated human lung mast cells (HLMCs) impair β2 -adrenoceptor (β2 -AR) function in human airway smooth muscle (ASM) cells. Protein array analysis confirmed the presence of various growth factors, including transforming growth factor (TGF)-β1, in the supernatants of high-affinity IgE receptor (FcεRI)-activated HLMCs which, when applied to ASM cells, impaired albuterol-induced cyclic adenosine monophosphate (cAMP) production, an effect that was prevented following neutralization of TGF-β1. This blunted β2 -AR response was reproduced by treating ASM cells with TGF-β1 or fibroblast growth factor (FGF)-2, which induced β2 -AR phosphorylation at tyrosine residues Tyr141 and Tyr350 , and significantly reduced the maximal bronchorelaxant responses to isoproterenol in human precision cut lung slices (PCLS). Finally, ASM cells isolated from severe asthmatics displayed constitutive elevated β2 -AR phosphorylation at both Tyr141 and Tyr350 and a reduced relaxant response to albuterol. This study shows for the first time that abnormal β2 -AR phosphorylation/function in ASM cells that is induced rapidly by HLMC-derived growth factors, is present constitutively in cells from severe asthmatics.