These authors contributed equally to this work.
Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3-kinase inhibition
Version of Record online: 25 SEP 2012
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society
British Journal of Pharmacology
Volume 167, Issue 4, pages 775–786, October 2012
How to Cite
Rossios, C., To, Y., Osoata, G., Ito, M., Barnes, P. and Ito, K. (2012), Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3-kinase inhibition. British Journal of Pharmacology, 167: 775–786. doi: 10.1111/j.1476-5381.2012.01864.x
- Issue online: 25 SEP 2012
- Version of Record online: 25 SEP 2012
- Accepted manuscript online: 17 JAN 2012 01:25PM EST
- Received; 24 July 2011; Revised; 22 December 2011; Accepted; 4 January 2012
- oxidative stress;
- severe asthma;
BACKGROUND AND PURPOSE Patients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids, which has been linked to oxidative stress. Here we show that the long-acting β2-agonist formoterol (FM) reversed corticosteroid insensitivity under oxidative stress via inhibition of phosphoinositide-3-kinase (PI3K) signalling.
EXPERIMENTAL APPROACH Responsiveness to corticosteroids dexamethasone (Dex), budesonide (Bud) and fluticasone propionate (FP) was determined, as IC50 values on TNF-α-induced interleukin 8 release, in U937 monocytic cell line treated with hydrogen peroxide (H2O2) or peripheral blood mononuclear cells (PBMCs) from patients with COPD or severe asthma.
KEY RESULTS PBMCs from severe asthma and COPD were less sensitive to Dex compared with those from healthy subjects. Both FM (10−9 M) and salmeterol (SM, 10−8 M) reversed Dex insensitivity in severe asthma, but only FM restored Dex sensitivity in COPD. Although H2O2 exposure decreased steroid sensitivity in U937 cells, FM restored responsiveness to Bud and FP while the effects of SM were weaker. Additionally, FM, but not SM, partially inhibited H2O2-induced PI3Kδ-dependent (PKB) phosphorylation. H2O2 decreased SM-induced cAMP production in U937 cells, but did not significantly affect the response to FM. The reduction of SM effects by H2O2 was reversed by pretreatment with LY294002, a PI3K inhibitor, or IC87114, a PI3Kδ inhibitor.
CONCLUSION AND IMPLICATIONS FM reversed oxidative stress-induced corticosteroid insensitivity and decreased β2 adrenoceptor-dependent cAMP production via inhibition of PI3Kδ signalling. FM will be more effective than SM, when combined with corticosteroids, for the treatment of respiratory diseases under conditions of high oxidative stress, such as in COPD.