title: Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Angelica
authors.initials: A
authors.lastname: Brandelius
authors.forename: Irma
authors.initials: I
authors.lastname: Mahmutovic Persson
authors.forename: Jenny
authors.initials: J
authors.lastname: Calvén
authors.forename: Leif
authors.initials: L
authors.lastname: Bjermer
authors.forename: Carl G A
authors.initials: CG
authors.lastname: Persson
authors.forename: Morgan
authors.initials: M
authors.lastname: Andersson
authors.forename: Lena
authors.initials: L
authors.lastname: Uller
mesh_terms: D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D003907:Dexamethasone; D019821:Simvastatin