Enhancement of inflammatory mediator release by beta(2)-adrenoceptor agonists in airway epithelial cells is reversed by glucocorticoid action.

Holden, Neil S. and Rider, C. F. and Bell, M. J. and Velayudhan, J. and King, E. M. and Kaur, M. and Salmon, M. and Giembycz, M. A. and Newton, R. (2010) Enhancement of inflammatory mediator release by beta(2)-adrenoceptor agonists in airway epithelial cells is reversed by glucocorticoid action. British journal of pharmacology, 160 (2). pp. 410-420. ISSN 0007-1188

Full content URL: http://dx.doi.org/10.1111/j.1476-5381.2010.00708.x

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Enhancement of inflammatory mediator release by beta(2)-adrenoceptor agonists in airway epithelial cells is reversed by glucocorticoid action

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Abstract

BACKGROUND AND PURPOSE

Due to their potent bronchodilator properties, beta(2)-adrenoceptor agonists are a mainstay of therapy in asthma. However, the effects of beta(2)-adrenoceptor agonists on inflammation are less clear. Accordingly, we have investigated the effects of beta(2)-adrenoceptor agonists on inflammatory mediator release.

EXPERIMENTAL APPROACH

Transcription factor activation, and both release and mRNA expression of IL-6 and IL-8 were examined by luciferase reporter assay, elisa and real-time RT-PCR in bronchial human epithelial BEAS-2B cells or primary human bronchial epithelial cells grown at an air-liquid interface.

KEY RESULTS

Pre-incubation with beta(2)-adrenoceptor agonists (salbutamol, salmeterol, formoterol) augmented the release and mRNA expression of IL-6 and IL-8 induced by IL-1beta and IL-1beta plus histamine, whereas NF-kappaB-dependent transcription was significantly repressed, and AP-1-dependent transcription was unaffected. These effects were mimicked by other cAMP-elevating agents (PGE(2), forskolin). Enhancement of cytokine release by beta(2)-adrenoceptor agonists also occurred in primary bronchial epithelial cells. Addition of dexamethasone with salmeterol repressed IL-6 and IL-8 release to levels that were similar to the repression achieved in the absence of salmeterol. IL-6 release was enhanced when salmeterol was added before, concurrently or after IL-1beta plus histamine stimulation, whereas IL-8 release was only enhanced by salmeterol addition prior to stimulation.

CONCLUSIONS AND IMPLICATIONS

Enhancement of IL-6 and IL-8 release may contribute to the deleterious effects of beta(2)-adrenoceptor agonists in asthma. As increased inflammatory mediator expression is prevented by the addition of glucocorticoid to the beta(2)-adrenoceptor, our data provide further mechanistic support for the use of combination therapies in asthma management.

Keywords:beta2-adrenoceptor agonists, Inflammation, IL-6, IL-8, Glucocorticoid, BEAS-2B epithelial cells, NHBE, Asthma
Subjects:B Subjects allied to Medicine > B210 Pharmacology
Divisions:College of Science > School of Life Sciences
ID Code:15119
Deposited On:23 Oct 2014 11:20

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