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J. Biol. Chem., Vol. 282, Issue 21, 15366-15375, May 25, 2007

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Corticosteroids and ₂ Agonists Differentially Regulate Rhinovirus-induced Interleukin-6 via Distinct Cis-acting Elements^*

Michael R. Edwards¹, Jennifer Haas, Rey A. Panettieri, Jr., Malcolm Johnson^¶, and Sebastian L. Johnston

From the Department of Respiratory Medicine, National Heart and Lung Institute and Wright Fleming Institute of Infection and Immunity, Imperial College London, London W2 1PG, United Kingdom MRC Centre in Allergic Mechanisms of Asthma, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, and ^¶GlaxoSmithKline, Middlesex, TW8 9GS, United Kingdom

Interleukin-6 (IL-6) is a proinflammatory cytokine up-regulated by rhinovirus infection during acute exacerbations of asthma and chronic obstructive pulmonary disease. The role of IL-6 during exacerbations is unclear; however, it is believed IL-6 could contribute to airway and systemic inflammation. In this study we investigate the effects of common asthma treatments fluticasone propionate and ₂ agonists salmeterol and salbutamol on IL-6 production in BEAS-2B and primary bronchial epithelial cells. Salmeterol and salbutamol enhanced rhinovirus- and IL-1-induced IL-6 production; however, fluticasone treatment caused a reduction of IL-6 protein and mRNA. Combined activity of salmeterol and fluticasone at equimolar concentrations had no effect on rhinovirus or IL-1 induction of IL-6. The induction of IL-6 by salmeterol was dependent upon the ₂ receptor and could also be induced by cAMP or cAMP-elevating agents forskolin and rolipram. Using transfection of IL-6 promoter reporter constructs, dominant negative mutants, and electromobility shift assays, it was found that NF-B was the only transcription factor required for rhinovirus induction of IL-6 gene expression. Salmeterol caused an augmentation of rhinovirus-induced promoter activation via a mechanism dependent upon the c/EBP and/or CRE (cyclic AMP response element) cis-acting sites. The suppressive effect of FP was dependent upon distinct glucocorticoid response element sequences proximal to the transcriptional start site within the IL-6 promoter. The data demonstrate that ₂ agonists can augment IL-6 expression by other stimuli in an additive manner via cyclic AMP and that the negative effect of steroids is mediated by glucocorticoid response elements within the IL-6 promoter.

Received for publication, February 15, 2007 , and in revised form, March 21, 2007.

^* This work was funded by an unrestricted grant from GlaxoSmithKline. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Respiratory Medicine, National Heart Lung Institute, St. Marys Hospital, Imperial College, London Norfolk Place, London W2 1PG, United Kingdom. Tel.: 44-207-594-3764; Fax: 44-207-262-8913; E-mail: michael.edwards{at}ic.ac.uk.

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