Downregulation by a long-acting β₂-adrenergic receptor agonist and corticosteroid of Staphylococcus aureus-induced airway epithelial inflammatory mediator production

Abstract

-Although Staphylococcus aureusis 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 NH 2-terminal kinase (JNK), and the P-isoform-␣ of the NF-B inhibitor (I B␣). 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-I B␣ 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 STAPHYLOCOCCUS AUREUS is one of the most common grampositive bacterial pathogens, involved in airway infections, either primary or subsequent to viral diseases (17). S. aureus is also a major cause of hospital-acquired lower respiratory tract infections and is often implicated in early infectious airway disease in cystic fibrosis patients (2, 5, 6, 22). S. aureus expresses several potential virulence factors (VF) that may induce airway epithelial injury, inactivate host defense mechanisms, and impair the epithelial wound/repair process. The increasing emergence of methicillin-resistant S. aureus requires a better understanding of staphylococcal pathogenesis in infectious and inflammatory airway diseases. S. aureus surface proteins such as adhesins and protein A are produced during exponential growth phase, whereas most exoproteins, including toxins, hemolysins, and tissue-degrading enzymes, are secreted during the stationary phase. Alpha-toxin, one of the major soluble VF of S. aureus, is able to induce transient apoptosis followed by the necrosis of human airway epithelial cells (HAEC) (9). We have also recently shown that live S. aureus and more predominantly soluble VF in contact with HAEC induce marked alterations in the transcriptional expression profile of HAEC associated with activation of the NF-B and activator protein (AP)-1 pathway, upregulation of PGE 2 and cyclooxygenase (COX)-2 expression and pr...

Induction of IL-8 expression by Cordyceps militaris grown on germinated soybeans through lipid rafts formation and signaling pathways via ERK and JNK in A549 cells

“…Therefore, the lack of an inhibitory effect of p38 kinase-inhibitors on the GSC4M-induced IL-8 expression implies that GSC4M could possibly induce synthesis of IL-8 mRNA rather than augmented stability of IL-8 mRNA. On the other hand, our results are coincident with a previous report showing that induction of IL-8 expression by Staphylococcus aureus is closely associated with ERK and JNK activation leading to the subsequent activation of NF-B and AP-1 transcription factors in human airway epithelial cells (Fragaki et al, 2006).…”

Seasonal Allergic Rhinitis Affects Sinonasal Microbiota

“…For example, steroids can effectively reduce bacteria-induced mucin expression in the airways 33 and can mitigate the proinflammatory responses to pathogens. 34 Dissecting these mechanisms would have broad implications for a range of diseases related to SAR, including asthma, perennial allergic rhinitis, and nonallergic rhinitis, in addition to ARS.…”

Impact of cigarette smoke exposure on host-bacterial pathogen interactions

“…Salmeterol has been shown to contribute to the protection of the airway epithelial barrier from P. aeruginosa [124]. The combination of salmeterol and fluticasone propionate has been shown to attenuate the inflammatory response of human airway epithelial cells infected with S. aureus [125]. Although salmeterol also seems to protect the respiratory epithelium against H. influenzae-induced damage [126], in vivo data show that inhalation of this bronchodilator may negatively influence the effective clearance of NTHi from the murine respiratory tract [127].…”