Differential effects of beta2-adrenoceptor desensitization on the IgE-dependent release of chemical mediators from cultured human mast cells

• Published in: Biological & pharmaceutical bulletin Vol. 27; no. 10; pp. 1549 - 1554
• Main Authors: Tsuji, Toshikazu, Kato, Toshinobu, Kimata, Masahiro, Miura, Toru, Serizawa, Isao, Inagaki, Naoki, Nagai, Hiroichi
• Format: Journal Article
• Language: English
• Published: Japan 2004
• Subjects: Actins - biosynthesis; Actins - genetics; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists - pharmacology; Cells, Cultured; Colforsin - pharmacology; Cyclic AMP - agonists; Cyclic AMP - biosynthesis; Histamine Release - drug effects; Humans; Immunoglobulin E - metabolism; Leukotriene D4 - antagonists & inhibitors; Mast Cells - drug effects; Mast Cells - metabolism; Prostaglandin D2 - antagonists & inhibitors; Receptors, Adrenergic, beta-2 - biosynthesis; Receptors, Adrenergic, beta-2 - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; Time Factors
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.27.1549

In the present study, we examined the inhibitory effects of the beta2-adrenoceptor agonists isoproterenol, salbutamol, fenoterol, and clenbuterol, on the release of chemical mediators from cultured human mast cells after prolonged treatment with the agonists. Although preincubation of sensitized mast cells for 10 min with beta2-adrenoceptor agonists potently inhibited mediator release, prolongation of the preincubation period up to 240 min attenuated the inhibition. The attenuation of histamine release inhibition was potent when compared with that of prostaglandin D2 (PGD2) and cysteinyl leukotriene (LT) release inhibition. In contrast, forskolin inhibited mediator release and the inhibition increased gradually in proportion to the preincubation period. The reduced inhibition by the beta2-adrenoceptor agonists was compensated for by simultaneous treatment with cholera toxin. The beta2-adrenoceptor agonists elevated intracellular cAMP levels after 10-min incubation and the elevated levels were almost comparable to those after 240-min incubation. Forskolin elevated the intracellular cAMP levels more potently after incubation for 240 min than after 10 min. When mast cells were incubated for 3 d with the beta2-adrenoceptor agonists, similar attenuation of mediator release inhibition was observed. Elevation of intracellular cAMP levels was also attenuated, although beta2-adrenoceptor mRNA expression was potentiated. The present results collectively indicate that the attenuation of mediator release inhibition by beta2-adrenoceptor agonists under the present experimental conditions involves uncoupling between beta2-adrenoceptors and Gs proteins. Furthermore, the beta2-adrenoceptor desensitization causes differential attenuating effects on the inhibition of histamine, PGD2, and LT release, suggesting that downstream events involved in each inhibitory pathway have different sensitivity to receptor desensitization.