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Endocrine Abstracts (2016) 44 S2.2 | DOI: 10.1530/endoabs.44.S2.2

SFEBES2016 Symposia Grappling with the future of anti-inflammatory steroids (3 abstracts)

Combination therapies that lighten the glucocorticoid load

Robert Newton


University of Calgary, Alberta, Canada.


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Glucocorticoids act on the glucocorticoid receptor (GR) and as inhaled corticosteroids (ICSs) effectively control mild to moderate asthma. However, during exacerbations, or more severe disease, ICS monotherapies are less effective and international guidelines recommend adding-on a long-acting β2-adrenoceptor agonist (LABA). ICS/LABA combination therapies provide superior asthma control and reduce exacerbation rates compared to increasing the ICS dose. This suggests a biological interaction between these drug classes. Indeed, LABAs synergistically enhance glucocorticoid-dependent transcription from a simple 2× glucocorticoid response element (GRE)-driven luciferase reporter. This effect occurs via a classical cAMP-protein kinase A (PKA)-dependent pathway and can be observed in human bronchial epithelial and airway smooth muscle cells. The effect is recapitulated using agonists of other Gs-coupled receptors, including PGE2, prostacyclin analogs and agonists at the adenosine A2 receptor. Similarly, phosphodiesterase (PDE) 4 inhibitors enhance GR-dependent transcription and sensitise to cAMP-elevating agents. Such approaches may be used to enhance GR action in systems whether the β2-adrenoreceptor coupling or expression is low.

Not only do LABAs enhance glucocorticoid-dependent transcription, but glucocorticoids enhance LABA-induced gene expression. Both these effects may contribute to the enhanced therapeutic efficacy of ICS/LABA combination therapies. Thus regulator of G-protein signalling 2 (RGS2), a GTPase-activating protein that reduces signalling from Gq-coupled receptors that are central to the pathogenesis of asthma, is induced by LABAs. This effect is enhanced by glucocorticoids to promote responses consistent with bronchoprotection. Conversely, TNFα inducible protein 3 (TNFAIP3), also known as A20, is an inhibitor of NF-κB and is induced by a glucocorticoid and this is further enhanced by a LABA. Glucocorticoid/LABA combination leads to enhanced TNFAIP3 expression to plays a role in the inhibition of NF-κB-dependent transcription. Mechanisms are therefore shown by which glucocorticoid/LABA combinations may promote enhanced bronchoprotective and anti-inflammatory effects that could help explain the clinical efficacy of ICS/LABA combination therapies.

Volume 44

Society for Endocrinology BES 2016

Brighton, UK
07 Nov 2016 - 09 Nov 2016

Society for Endocrinology 

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