These authors contributed equally.
Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors
Article first published online: 20 DEC 2012
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Endothelin. Guest Editors: Anthony P Davenport and Matthias Barton
Volume 168, Issue 2, pages 363–374, January 2013
How to Cite
Brandelius, A., Mahmutovic Persson, I., Calvén, J., Bjermer, L., Persson, C. G., Andersson, M. and Uller, L. (2013), Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors. British Journal of Pharmacology, 168: 363–374. doi: 10.1111/j.1476-5381.2012.02131.x
- Issue published online: 20 DEC 2012
- Article first published online: 20 DEC 2012
- Accepted manuscript online: 6 AUG 2012 07:34AM EST
- Manuscript Accepted: 30 JUL 2012
- Manuscript Revised: 11 JUL 2012
- Manuscript Received: 4 APR 2012
- Vinnova, Swedish Heart and Lung foundation
- Crafoord Foundation
- bronchial brushing epithelium;
- mevalonate independent;
- IRF3 phosphorylation;
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.
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 μg·mL−1). Cells were treated with simvastatin (0.2–5 μg·mL−1), with or without mevalonate (13–26 μg·mL−1), or dexamethasone (1 μg·mL−1) before dsRNA. Cytokine expression and production, and transcription factor (IRF3 and NF-κB) activation were determined.
dsRNA induced TSLP, TNF-α, CXCL8 and IFN-β. 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-κB activation nor did it reduce production of TNF-α and CXCL8. Instead, simvastatin inhibited dsRNA-induced IRF3 phosphorylation and generation of IFN-β.
Conclusions and Implications
Independent of mevalonate and NF-κB, previously acknowledged anti-inflammatory mechanisms of pleiotropic statins, simvastatin selectively inhibited dsRNA-induced IRF3 activation and production of TSLP and IFN-β 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.