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-1) 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.
Adcock
I M
IM
Dept of Thoracic Medicine, Imperial College of Science, Technology & Medicine, London, UK.
Stevens
D A
DA
Barnes
P J
PJ
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy; D000242:Cyclic AMP / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D005938:Glucocorticoids; D018343:Receptors, Adrenergic, beta-2; D014157:Transcription Factors; D000242:Cyclic AMP