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Glucocorticoids reverse IL‐1β‐induced impairment of β‐adrenoceptor‐mediated relaxation and up‐regulation of G‐protein‐coupled receptor kinases
Author(s) -
Mak Judith C W,
Hisada Takeshi,
Salmon Michael,
Barnes Peter J,
Chung K Fan
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704545
Subject(s) - endocrinology , medicine , forskolin , adenylyl cyclase , dexamethasone , bronchoconstriction , glucocorticoid , agonist , clenbuterol , chemistry , ex vivo , in vivo , glucocorticoid receptor , isoprenaline , receptor , biology , in vitro , stimulation , asthma , biochemistry , microbiology and biotechnology
The aim of the present study was to examine the effects of glucocorticoid dexamethasone on airway responsiveness to albuterol after intratracheal instillation of saline or IL‐1β in Brown‐Norway rats in vivo and to elucidate the molecular mechanism of this effect. IL‐1β caused a significant reduction in albuterol‐mediated relaxation to protect against MCh‐induced bronchoconstriction. Dexamethasone attenuated the IL‐1β‐induced impaired relaxation while alone had no effect when compared to rats treated identically with saline. The density of β 2 ‐adrenoceptors was significantly reduced in lung membranes harvested from IL‐1β‐treated rats, which was associated with impaired isoproterenol‐ and forskolin‐stimulated cyclic AMP accumulation and adenylyl cyclase (AC) activity ex vivo . Dexamethasone did not prevent IL‐1β‐induced down‐regulation of β 2 ‐adrenoceptors but completely blocked IL‐1β‐induced impairment of cyclic AMP accumulation and AC activity stimulated by isoproterenol and forskolin. The inhibitory G‐protein subtypes, G iα1 , G iα2 and G iα3 , were detected in lung membranes prepared from all groups of rats but the intensity of G iα1 and G iα2 was markedly increased in IL‐1β‐treated rats, which were not prevented by dexamethasone. The activity of cytosolic GRK and the expression of GRK2 and GRK5 were elevated in the lung of IL‐1β‐treated rats, which were completely abolished by dexamethasone. These results indicate that treatment of rats with IL‐1β results in desensitization of pulmonary β 2 ‐adrenoceptors. In light of data obtained in this study, we propose that both the decrease in AC activity and the increase in GRK activity, which are reversed by dexamethasone, may underlie β 2 ‐adrenoceptor desensitization.British Journal of Pharmacology (2002) 135 , 987–996; doi: 10.1038/sj.bjp.0704545