Interactions of glucocorticoids and beta(2)-agonists

Beta(2)-adrenoreceptor agonists and glucocorticosteroids are the two most effective treatments for asthma and are often used in combination, Glucocorticoids mediate their anti-inflammatory effects through the action of activated glucocorticoid receptors (GRs), Many of the effects of GRs on the synthesis of cytokines and other inflammatory mediators are due to a direct interaction with other deoxyribonucleic acid (DNA)-binding proteins belonging to the basic leucine zipper (bZIP) group of transcription factors, such as activator protein-1 (AP-I) and nuclear factor-kappa B (NF-kappa B). Beta(2)-agonists are potent bronchodilators at low doses and at high doses can activate gene transcription via a bZIP protein, cyclic adenosine monophosphate (cAMP) response element binding protein(CREB), Activated GRs and CREB can interact with each other within the nucleus to modulate both DNA-binding and gene transcription in either a positive or inhibitory manner, depending on cell type, In lung cells, high doses of beta(2)-agonists reduce the ability of GR to bind DNA, a process which is mediated by CREB activation, Inhibition of GR DNA-binding by CREB raises the possibility that high-dose beta(2)-agonists could have functional antiglucocorticoid activity and may be a basis for the reported increase in asthma morbidity and mortality in industrialized countries, which have increasing per capita beta(2)-agonist use.