Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors

BACKGROUND AND PURPOSE Statin treatment may ameliorate viral infection-induced exacerbations of chronic obstructive pulmonary disease (COPD), which exhibit Th2-type bronchial inflammation. Thymic stromal lymphopoietin (TSLP), a hub cytokine switching on Th2 inflammation, is overproduced in viral and dsRNA-stimulated bronchial epithelial cells from COPD donors. Hence, TSLP may be causally involved in exacerbations. This study tests the hypothesis that simvastatin inhibits dsRNA-induced TSLP. EXPERIMENTAL APPROACH Epithelial cells, obtained by bronchoscopy from COPD (n = 7) and smoker control (n = 8) donors, were grown and stimulated with a viral infection and danger signal surrogate, dsRNA (10 mu g.mL(-1)). Cells were treated with simvastatin (0.2-5 mu g.mL(-1)), with or without mevalonate (13-26 mu g.mL(-1)), or dexamethasone (1 mu g.mL(-1)) before dsRNA. Cytokine expression and production, and transcription factor (IRF3 and NF-kappa B) activation were determined. KEY RESULTS dsRNA induced TSLP, TNF-alpha, CXCL8 and IFN-beta. TSLP was overproduced in dsRNA-exposed COPD cells compared with control. Simvastatin, but not dexamethasone, concentration-dependently inhibited dsRNA-induced TSLP. Unexpectedly, simvastatin acted independently of mevalonate and did not affect dsRNA-induced NF-kappa B activation nor did it reduce production of TNF-alpha and CXCL8. Instead, simvastatin inhibited dsRNA-induced IRF3 phosphorylation and generation of IFN-beta. CONCLUSIONS AND IMPLICATIONS Independent of mevalonate and NF-kappa B, previously acknowledged anti-inflammatory mechanisms of pleiotropic statins, simvastatin selectively inhibited dsRNA-induced IRF3 activation and production of TSLP and IFN-beta in COPD epithelium. These data provide novel insight into epithelial generation of TSLP and suggest paths to be exploited in drug discovery aimed at inhibiting TSLP-induced pulmonary immunopathology.