Interactions iith Other Signaling Mechanisms
Molecular interactions between glucocorticoids and long-acting β2-agonists,☆☆

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Abstract

β2-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 κB. GR functions such as nuclear localization and gene activation can be regulated by phosphorylation status. Long-acting β2-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 β2-adrenergic receptor function by increasing its expression, acting through glucocorticoid response elements, and, importantly, by restoring G-protein-β2-receptor coupling and inhibiting β2-receptor downregulation, thereby preventing desensitization. (J Allergy Clin Immunol 2002;110:S261-8.)

Section snippets

Mechanisms of glucocorticoid action

Endogenous glucocorticoids regulate the body's normal reactions to stress, preventing those reactions from overshooting and threatening homeostasis.4 Thus, many of the physiologic and pharmacologic effects of glucocorticoids may be secondary to modulation of the action of numerous intercellular and intracellular mediators, including other hormones, prostaglandins, lymphokines, and bioactive peptides.5 Glucocorticoids act by influencing transcription of target genes.6 Glucocorticoids freely

Effects of GR phosphorylation status on GR function

GR is a phosphoprotein containing 64 potential phosphorylation sites,13 including those for extracellular signal-regulated kinase (ERK, 8 sites), p38 mitogen-activated protein kinase (MAPK, 1 site), glycogen synthase kinase-3 (8 sites), protein kinase C (PKC, 9 sites), and protein kinase A (PKA, 8 sites). Importantly, GR has 3 ERK binding sites (Fig 2).

. Potential phosphorylation sites on GR. Some of the possible PKA, glycogen synthase kinase-3 (GSK-3), PKC, and ERK phosphorylation sites are

Mechanisms of β-Agonist action

Ligand binding to the β2-adrenergic receptor (β2AR) results in activation of receptor-associated Gs proteins and enhanced coupling with adenylyl cyclase.3 The coupling of activated Gs and adenylyl cyclase leads to enhanced production of cyclic AMP (cAMP) and subsequent activation of cAMP-dependent PKA, which then phosphorylates and thus inactivates myosin light chain kinase, preventing myosin phosphorylation. Concomitant activation of calcium-magnesium exchange ATPases in the endoplasmic

Effects of LABA on GR function: possible role of GR phosphorylation

In an important in vitro study, Eickelberg et al38 found that in primary human lung fibroblasts and vascular smooth muscle cells both salbutamol and salmeterol could induce GR nuclear translocation and enhance GR-GRE binding in the absence of ligand. Translocation of GR by β2-agonists was less effective than that seen with dexamethasone and was PKA dependent. This study has since been confirmed in preliminary reports in vivo,39, 40, 41 which have indicated that salmeterol can induce GR nuclear

Up-regulation of receptor number

Dexamethasone, a synthetic glucocorticoid, increases the number of β2ARs in human lung measured by radioligand binding.46 Several putative GREs have been identified in the promoter sequence of the human β2AR gene,47 and increased β2AR gene transcription occurs after dexamethasone treatment through a GRE in the 5′-flanking region of the gene36 in human lung tissue. This increase in transcription is both time-dependent and dose-dependent, consistent with the later induction of receptor binding

Conclusions

LABAs may affect GR nuclear localization through modulation of GR phosphorylation and, further, may prime GR functions within the nucleus by modifying GR or GR-associated protein phosphorylation. Glucocorticoids may in turn regulate β2AR function by increasing expression, acting through GREs, and, importantly, by restoring G-protein-β2AR coupling and inhibiting β2-AR down-regulation, thereby preventing desensitization.

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    Work within the laboratory is funded by The Clinical Research Committee (Royal Brompton Hospital), The British Lung Foundation, GlaxoSmith-Kline, and Innovata Biomed. K.M. is funded by the Thai Government, and O.U. is funded by GlaxoSmithKline.

    ☆☆

    Reprint requests: Ian M. Adcock, PhD, Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Dovehouse St, London SW3 6LY, UK.

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