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Interactions Between Corticosteroids and Β Agonists Thorax 2000;55:595–602 595 Occasional reviews Interactions between corticosteroids and â agonists Department of Medicine, Dunedin D R Taylor, R J Hancox School of Medicine, P O Box 913, Dunedin, New Zealand D R Taylor Inhaled corticosteroids and â agonists are the whereas long acting agents are indicated as a R J Hancox most frequently prescribed drugs in the supplement to anti-inflammatory therapy if management of chronic asthma. Current breakthrough symptoms persist.1 Thus, co- Correspondence to: prescribing is commonplace. However, despite Dr D R Taylor guidelines emphasise their complementary e-mail: robin.taylor@ role. Inhaled corticosteroids are the treatment dynamic interactions between endogenous stonebow.otago.ac.nz of choice for all but the mildest of disease. glucocorticoids and catecholamines in vivo, it Received 5 January 2000 Short acting â agonists are recommended for is only recently that interest in the possibility of Accepted for publication “as required” relief of asthma symptoms, drug interactions has developed. Two topical 20 January 2000 and clinically relevant questions arise. Firstly, do positive interactions occur, thus providing s BA theoretical justification for current trends to use combination products incorporating a long Gs BR acting â agonist and a corticosteroid? Sec- AC ondly, do negative interactions occur which might explain the apparent paradox that, HSP GR 1 ATP despite increasing use of the two therapies over the last 30 years, the overall burden of asthma cAMP HSP s 2 morbidity in most western countries has GR CREB continued to increase?2 TF 3 EVects of glucocorticoids on â receptor PKA 10 function s 4 Endogenous adrenal glucocorticoids have an GR CREB important facilitatory eVect on â receptor 6 function in vivo. In animals adrenalectomy 5 results in a generalised loss of responsiveness to CBP catecholamines.34 Conversely, the presence of RP GR 9 mRNA glucocorticoids enhances â receptor mediated responses: myocardial contractility, hepatic and DNA GRE CRE Gene voluntary muscle glucose metabolism, and 8 bronchial smooth muscle relaxation have been 4 7 BR shown to increase. These actions occur at mRNA physiological concentrations of glucocorticoid. At least two mechanisms are proposed whereby glucocorticoids modify â receptor function. The first is by regulating the coupling Figure 1 Putative intracellular mechanisms for interaction between â agonists and of â receptors to G proteins and hence adenyl corticosteroids. (1) The steroid-glucocorticoid receptor complex upregulates â2 receptors by cyclase activation (fig 1). The degree of enhancing receptor coupling with G protein and/or preventing downregulation following â2 coupling determines cell responsiveness to â â2 receptor activation. (2) Binding between the activated glucocorticoid receptor and CREB 5 in the cytoplasm may inhibit translocation to the nucleus. (3) “Cross talk” between the receptor stimulation. Following exposure to glucocorticoid receptor, CREB, and other nuclear transcription factors. (4) “Cross talk” exogenous â agonist, uncoupling occurs rap- between the glucocorticoid receptor and CREB in the nucleus. (5) The glucocorticoid idly by phosphorylation of the receptor (desen- receptor and CREB may compete for or synergistically bind protein co-factors such as CBP which are required for coupling with RNA polymerase and activation of response elements sitisation). There are a number of phosphoryla- in the promoter regions of target genes. (6) Direct phosphorylation of protein co-factors such tion pathways, including â adrenoceptor kinase as CBP may alter their activity. (7) The presence of both GREs and CREs in the promoter (â-ARK),67 and these constitute the first step regions of target genes may mutually enhance or inhibit their eVects on gene transcription. towards the development of drug tolerance. (8) The promoter region of the â receptor gene contains GREs which may enhance or 2 Exposure to corticosteroids restores receptors suppress synthesis of the â2 receptor protein. (9) The promoter region of the glucocorticoid receptor gene contains CREs which may enhance or suppress synthesis of the glucocorticoid to their previously sensitised state.8 receptor protein. (10) A cAMP-dependent mechanism enhances the stability of messenger The second is that glucocorticoids can RNA for the glucocorticoid receptor increasing receptor levels.17 AC = adenylate cyclase; upregulate previously downregulated â receptor ATP = adenosine triphosphate; BA = â agonist; BR = â2 adrenoceptor; CBP = CREB binding protein; CRE = cAMP response element; CREB = cAMP response element binding function after chronic â agonist exposure. protein; cAMP = cyclic adenosine monophosphate; GR = glucocorticoid receptor; GRE = Downregulation is characterised by receptor glucocorticoid response element; Gs = stimulatory G protein; HSP = heat shock protein 90; 9 mRNA = messenger RNA; PKA = protein kinase A; RP = RNA polymerase; S = steroid internalisation and degradation, reversal of drug molecule; TF = transcription factor. which requires new receptor synthesis. Activa- 596 Taylor, Hancox tion of glucocorticoid response elements factor NF-êB was reduced in bronchial mu- (GREs) in the promoter region of the â receptor cosa and GR binding increased with regular gene causes an increase in the rate of gene tran- inhaled budesonide, the simultaneous adminis- scription and hence of receptor numbers.10–15 tration of regular terbutaline did not alter the binding activity of either.24 EVects of â agonists on glucocorticoid In other studies in human bronchial epithe- receptor function lial cells an inhibitory eVect of terbutaline on Inactive glucocorticoid receptors (GRs) are GR binding responses to budesonide has been bound to protein complexes (including heat shown, but occurred only when the â agonist shock protein, HSP-90) in the cytosol. After was administered simultaneously; the eVects of ligand binding, activated GRs dissociate and prior exposure to corticosteroid were unaf- translocate to the nucleus where they bind to fected by the subsequent addition of glucocorticoid response elements (GREs) in terbutaline.25 Thus, the timing of exposure to the promoter region of target genes. The eVect the two agents may be of relevance in of catecholamines on the normal function of determining possible interactions. In contrast, GRs and GREs has not been studied in detail. in another study both salbutamol and sal- Forskolin, which increases intracellular cyclic meterol have been shown to enhance the AMP levels (thereby mimicking â2 receptor activation of GC receptors and their binding to activation), has been shown to increase rat nuclear GREs.26 hepatoma cell GR numbers and potentiate the The results of other laboratory studies production of dexamethasone induced neuro- designed to evaluate possible interactions tensin from the rat hypothalamic cells.16 between â agonists and glucocorticoids on Forskolin may also antagonise the downregula- inflammatory cells and their cytokines have tion of GRs induced by dexamethasone.17 also been inconsistent. Salmeterol has been These actions provide indirect evidence that â shown to enhance the steroid induced inhibi- agonists, which also enhance intracellular tion of allergen activated monocytes27 and also cAMP levels, might enhance GR function. appears to potentiate fluticasone induced Glucocorticoids mediate many of their anti- apoptosis in activated human eosinophils (by a inflammatory eVects by either activating or factor of 2–3).28 Similarly, in airway smooth repressing gene transcription of cytokines. In muscle cells the inhibitory eVect of dexametha- addition to the binding of activated GRs to sone on tumour necrosis factor (TNF)-á GREs in the nucleus, this may also occur indi- mediated interleukin-8 production was poten- rectly when activated GRs interact with pro- tiated by simultaneous incubation with both inflammatory nuclear transcription factors—for salbutamol and salmeterol.29 In contrast, Sel- example, AP-1 or NF-kappa B (NF-êB)—to don et al have studied the eVect of salbutamol suppress their eVects on the upregulation of on dexamethasone induced inhibition of pro-inflammatory cytokine production (fig TNF-á and GM-CSF production from stimu- 1).18 19 Beta agonists modify gene transcription lated monocytes but, even at high concentra- by increasing intracellular levels of cAMP and tions of salbutamol, no important interaction activating the nuclear transcription factor was observed.30 Other in vitro data suggest that, cAMP response element binding protein at pharmacological concentrations, the pres- (CREB). In turn this binds to cAMP response ence of either isoprenaline or salbutamol may elements (CREs) on target genes. So-called actually impair the beneficial actions of steroid. “cross talk” between these transcription factors Nielson et al31 have shown that the eVects of has been postulated as a mechanism for dexamethasone on eosinophil superoxide pro- interactions between â agonist and cortico- duction and apoptosis are reduced in a dose steroid drugs. It is likely that “cross talk” dependent manner by both of these short includes competitive binding of protein co- acting â agonists. factors such as CREB binding protein (CBP) or A number of biological and pharmacological the related P300 which are necessary for the factors might account for the apparently activation of transcription factor response conflicting outcomes from these studies. They elements to GRs.20 Interactions between GREs include tissue dependent diVerences
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