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TRANSLATIONAL PHYSIOLOGY

Downregulation by a long-acting ₂-adrenergic receptor agonist and corticosteroid of Staphylococcus aureus-induced airway epithelial inflammatory mediator production

INSERM, Unité Mixte de Recherches 514, Institut Fédératif de Recherche (IFR) 53, Centre Hospitalier Universitaire Maison Blanche, Reims, France; ²Laboratoire d’Onco-Pharmacologie, Jeune Equipe 2428, IFR 53, Unité de Formation et de Recherche de Pharmacie, Université de Reims Champagne-Ardenne, Reims, France; and ³GlaxoSmithKline Research and Development, Middlesex, United Kingdom

Submitted 17 November 2005 ; accepted in final form 14 February 2006

Although Staphylococcus aureus is a major cause of pulmonary infection, the role played by this bacterium in the induction of inflammation of human airway epithelial cells (HAEC) is poorly understood. In this study, we investigated the inflammatory response of HAEC to S. aureus soluble virulence factors and demonstrate that the combination of a long-acting ₂-adrenergic receptor agonist (salmeterol) with a glucocorticoid (fluticasone propionate) has an anti-inflammatory effect on HAEC. First, we demonstrate increased expression at both the mRNA and protein levels of interleukin (IL)-8, IL-6, and tumor necrosis factor (TNF)- following incubation of HAEC in the presence of S. aureus soluble virulence factors and the increase of 1) the free nuclear factor-B (NF-B) and activator protein-1 (AP-1) activities and 2) the phosphorylated (P-) extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2), the P-c-Jun NH₂-terminal kinase (JNK), and the P-isoform- of the NF-B inhibitor (IB). Next, when HAEC were preincubated with the combination of salmeterol and fluticasone propionate, the inflammatory response of HAEC was markedly attenuated in that levels of IL-8, IL-6, TNF-, NF-B, AP-1, P-ERK1/ERK2, P-JNK, and P-IB decreased significantly. These data emphasize the deleterious effect of S. aureus soluble virulence factors and suggest that the combination of a ₂-adrenergic receptor agonist with a glucocorticoid may attenuate the associated airway epithelial inflammation.

airway inflammation; proinflammatory cytokines; nuclear fator-B and activator protein-1 activation; glucocorticoid; bacterial virulence factors

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