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

Br J Pharmacol. 2013 Jan;168(2):363-74. doi: 10.1111/j.1476-5381.2012.02131.x.


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 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.

Key results: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Inflammatory Agents / pharmacology
  • Bronchi / cytology
  • Cells, Cultured
  • Cytokines / antagonists & inhibitors*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Dexamethasone / pharmacology
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Interferon Regulatory Factor-3 / antagonists & inhibitors*
  • Interferon Regulatory Factor-3 / metabolism
  • Male
  • Middle Aged
  • NF-kappa B / metabolism
  • Phosphorylation / drug effects
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • RNA, Double-Stranded / pharmacology*
  • Simvastatin / pharmacology*


  • Anti-Inflammatory Agents
  • Cytokines
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • NF-kappa B
  • RNA, Double-Stranded
  • Dexamethasone
  • Simvastatin