Protection by dexamethasone of the functional desensitization to beta 2-adrenoceptor-mediated responses in human lung mast cells.
1. The beta-adrenoceptor agonist, isoprenaline, inhibited the IgE-mediated release of histamine from human lung mast cells (HLMC) in a dose-dependent manner. Maximal inhibitory effects were obtained with 0.1 microM isoprenaline. However, the inhibition of histamine release from HLMC by isoprenaline (0.1 microM) was highly variable ranging from 33 to 97% inhibition (mean, 59 +/- 3%, n = 27). 2. Long-term (24 h) incubation of HLMC with isoprenaline led to a subsequent reduction in the ability of a second exposure of isoprenaline to inhibit IgE-mediated histamine release from HLMC. The impairment in the ability of isoprenaline (0.1 microM) to inhibit histamine release following desensitizing conditions (1 microM isoprenaline for 24 h) was highly variable amongst HLMC preparations ranging from essentially negligible levels of desensitization in some preparations to complete abrogation of the inhibitory response in others (mean, 65 +/- 6% desensitization, n = 27). 3. The ability of HLMC to recover from desensitization was investigated. Following desensitizing conditions (1 microM isoprenaline for 24 h), HLMC were washed and incubated for 24 h in buffer and the effectiveness of isoprenaline (0.1 microM) to inhibit IgE-mediated histamine release from HLMC was assessed. The extent of recovery was highly variable with some HLMC preparations failing to recover and others displaying a complete restoration of responsiveness to isoprenaline (mean, 40 +/- 6% recovery, n = 23). 4. The effects of the glucocorticoid, dexamethasone, were also investigated. Long-term (24-72 h) treatments with dexamethasone (0.1 microM) had no effect on IgE-mediated histamine release from HLMC. Additionally, long-term (24-72 h) treatments with dexamethasone (0.1 microM) had no effect on the effectiveness of isoprenaline to inhibit histamine release. However, long-term (24-72 h) treatments with dexamethasone (0.1 microM) protected against the functional desensitization induced by incubation (24 h) of HLMC with isoprenaline (1 microM). The protective effect was time-dependent and pretreatment of HLMC with dexamethasone for either 24, 48 or 72 h prevented desensitization by either 15 +/- 7, 19 +/- 5 or 51 +/- 10%, respectively (n = 5-7). 5. HLMC preparations which were relatively refractory to isoprenaline even after withdrawal (24 h) from desensitizing conditions responded more effectively to isoprenaline (0.1 microM) if dexamethasone (0.1 microM) was also included during the recovery period (19 +/- 9% recovery after 24 h in buffer; 50 +/- 8% recovery after 24 h with dexamethasone, n = 5). 6. These data indicate that the responses of different HLMC preparations to isoprenaline, the susceptibility of HLMC to desensitization and the ability of HLMC to recover from desensitizing conditions varies markedly. Dexamethasone, which itself has no direct effects on IgE-mediated histamine release from HLMC, protected HLMC from the functional desensitization to beta-adrenoceptor agonists. Because beta 2-adrenoceptor agonists and glucocorticoids are important in the therapeutic management of asthma and as the HLMC is probably important in certain types of asthma, these findings may have wider clinical implications.
Chong
L K
LK
Department of Medicine & Pharmacology, University of Sheffield, Royal Hallamshire Hospital, Sheffield.
Drury
D E
DE
Dummer
J F
JF
Ghahramani
P
P
Schleimer
R P
RP
Peachell
P T
PT
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003888:Desensitization, Immunologic; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D008407:Mast Cells / Q000187:drug effects*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D018343:Receptors, Adrenergic, beta-2; D003907:Dexamethasone; D007545:Isoproterenol