Molecular interactions between glucocorticoids and long-acting beta2-agonists

Abstract

beta(2)-Adrenergic receptor agonists and glucocorticoids are the two most effective treatments for asthma, and used in combination they are more effective than either alone. Glucocorticoids mediate their anti-inflammatory effects through the action of activated glucocorticoid receptors (GRs), with the level of activity being related to the number of nuclear receptors. Glucocorticoids can upregulate the synthesis of several genes in human lung cells through interaction with specific DNA binding regions (glucocorticoid response elements) within the promoter region of glucocorticoid-responsive genes. Many of the down-regulating effects of GRs on the synthesis of cytokines and other inflammatory mediators are due to repression of other transcription factors, such as activator protein-1 and nuclear factor kappaB. GR functions such as nuclear localization and gene activation can be regulated by phosphorylation status. Long-acting beta(2)-agonists may affect GR nuclear localization through modulation of GR phosphorylation and furthermore through priming of GR functions within the nucleus by modifying GR or GR-associated protein phosphorylation. Glucocorticoids in turn may regulate beta(2)-adrenergic receptor function by increasing its expression, acting through glucocorticoid response elements, and, importantly, by restoring G-protein-beta(2)-receptor coupling and inhibiting beta(2)-receptor downregulation, thereby preventing desensitization.