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Selective inhibition by simvastatin of IRF 3 phosphorylation and TSLP production in dsRNA ‐challenged bronchial epithelial cells from COPD donors
Author(s) -
Brandelius Angelica,
Mahmutovic Persson Irma,
Calvén Jenny,
Bjermer Leif,
Persson Carl GA,
Andersson Morgan,
Uller Lena
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02131.x
Subject(s) - irf3 , simvastatin , cytokine , immunology , rna silencing , irf7 , inflammation , thymic stromal lymphopoietin , biology , medicine , pharmacology , immune system , rna , rna interference , innate immune system , biochemistry , gene
Background and Purpose Statin treatment may ameliorate viral infection‐induced exacerbations of chronic obstructive pulmonary disease ( COPD ), which exhibit Th 2‐type bronchial inflammation. Thymic stromal lymphopoietin ( TSLP ), a hub cytokine switching on Th 2 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 ( IRF 3 and NF ‐κ B ) activation were determined. Key Results dsRNA induced TSLP , TNF ‐α, CXCL 8 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 ‐κ B activation nor did it reduce production of TNF ‐α and CXCL 8. Instead, simvastatin inhibited dsRNA ‐induced IRF 3 phosphorylation and generation of IFN ‐β. Conclusions and Implications Independent of mevalonate and NF ‐κ B , previously acknowledged anti‐inflammatory mechanisms of pleiotropic statins, simvastatin selectively inhibited dsRNA ‐induced IRF 3 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.