Glucocorticoids reverse IL-1beta-induced impairment of beta-adrenoceptor-mediated relaxation and up-regulation of G-protein-coupled receptor kinases

Br J Pharmacol. 2002 Feb;135(4):987-96. doi: 10.1038/sj.bjp.0704545.

Abstract

1. 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-1beta in Brown-Norway rats in vivo and to elucidate the molecular mechanism of this effect. 2. IL-1beta caused a significant reduction in albuterol-mediated relaxation to protect against MCh-induced bronchoconstriction. Dexamethasone attenuated the IL-1beta-induced impaired relaxation while alone had no effect when compared to rats treated identically with saline. 3. The density of beta(2)-adrenoceptors was significantly reduced in lung membranes harvested from IL-1beta-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-1beta-induced down-regulation of beta(2)-adrenoceptors but completely blocked IL-1beta-induced impairment of cyclic AMP accumulation and AC activity stimulated by isoproterenol and forskolin. 4. The inhibitory G-protein subtypes, G(ialpha1), G(ialpha2) and G(ialpha3), were detected in lung membranes prepared from all groups of rats but the intensity of G(ialpha1) and G(ialpha2) was markedly increased in IL-1beta-treated rats, which were not prevented by dexamethasone. 5. The activity of cytosolic GRK and the expression of GRK2 and GRK5 were elevated in the lung of IL-1beta-treated rats, which were completely abolished by dexamethasone. 6. These results indicate that treatment of rats with IL-1beta results in desensitization of pulmonary beta(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 beta(2)-adrenoceptor desensitization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Blotting, Northern
  • Cyclic AMP / biosynthesis
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dexamethasone / pharmacology*
  • G-Protein-Coupled Receptor Kinase 3
  • G-Protein-Coupled Receptor Kinase 5
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • GTP-Binding Proteins / metabolism*
  • Glucocorticoids / pharmacology*
  • Interleukin-1 / pharmacology*
  • Lung / drug effects
  • Lung / metabolism
  • Lung / physiology
  • Male
  • Muscle Relaxation / drug effects
  • Protein Isoforms / metabolism
  • Protein Kinases / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Radioligand Assay
  • Rats
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Up-Regulation
  • beta-Adrenergic Receptor Kinases

Substances

  • Adrenergic beta-Agonists
  • Glucocorticoids
  • Interleukin-1
  • Protein Isoforms
  • Receptors, Adrenergic, beta-2
  • Dexamethasone
  • Cyclic AMP
  • Protein Kinases
  • Protein Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • G-Protein-Coupled Receptor Kinase 3
  • Grk3 protein, rat
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinase 5
  • Grk5 protein, rat
  • GTP-Binding Proteins
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Adenylyl Cyclases