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Thymic stromal lymphopoietin (TSLP<\/jats:styled-content>), a hub cytokine switching on Th<\/jats:styled-content>2 inflammation, is overproduced in viral and dsRNA<\/jats:styled-content>\u2010stimulated bronchial epithelial cells from COPD<\/jats:styled-content> donors. Hence, TSLP<\/jats:styled-content> may be causally involved in exacerbations. This study tests the hypothesis that simvastatin inhibits dsRNA<\/jats:styled-content>\u2010induced TSLP<\/jats:styled-content>.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>Epithelial cells, obtained by bronchoscopy from COPD<\/jats:styled-content> (n<\/jats:italic> = 7) and smoker control (n<\/jats:italic> = 8) donors, were grown and stimulated with a viral infection and danger signal surrogate, dsRNA<\/jats:styled-content> (10\u2009\u03bcg\u00b7mL\u22121<\/jats:sup>). Cells were treated with simvastatin (0.2\u20135\u2009\u03bcg\u00b7mL\u22121<\/jats:sup>), with or without mevalonate (13\u201326\u2009\u03bcg\u00b7mL\u22121<\/jats:sup>), or dexamethasone (1\u2009\u03bcg\u00b7mL\u22121<\/jats:sup>) before dsRNA<\/jats:styled-content>. Cytokine expression and production, and transcription factor (IRF<\/jats:styled-content>3 and NF<\/jats:styled-content>\u2010\u03baB<\/jats:styled-content>) activation were determined.<\/jats:p><\/jats:sec>Key Results<\/jats:title>dsRNA<\/jats:styled-content> induced TSLP<\/jats:styled-content>, TNF<\/jats:styled-content>\u2010\u03b1, CXCL<\/jats:styled-content>8 and IFN<\/jats:styled-content>\u2010\u03b2. TSLP<\/jats:styled-content> was overproduced in dsRNA<\/jats:styled-content>\u2010exposed COPD<\/jats:styled-content> cells compared with control. Simvastatin, but not dexamethasone, concentration\u2010dependently inhibited dsRNA<\/jats:styled-content>\u2010induced TSLP<\/jats:styled-content>. Unexpectedly, simvastatin acted independently of mevalonate and did not affect dsRNA<\/jats:styled-content>\u2010induced NF<\/jats:styled-content>\u2010\u03baB<\/jats:styled-content> activation nor did it reduce production of TNF<\/jats:styled-content>\u2010\u03b1 and CXCL<\/jats:styled-content>8. Instead, simvastatin inhibited dsRNA<\/jats:styled-content>\u2010induced IRF<\/jats:styled-content>3 phosphorylation and generation of IFN<\/jats:styled-content>\u2010\u03b2.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>Independent of mevalonate and NF<\/jats:styled-content>\u2010\u03baB<\/jats:styled-content>, previously acknowledged anti\u2010inflammatory mechanisms of pleiotropic statins, simvastatin selectively inhibited dsRNA<\/jats:styled-content>\u2010induced IRF<\/jats:styled-content>3 activation and production of TSLP<\/jats:styled-content> and IFN<\/jats:styled-content>\u2010\u03b2 in COPD<\/jats:styled-content> epithelium. These data provide novel insight into epithelial generation of TSLP<\/jats:styled-content> and suggest paths to be exploited in drug discovery aimed at inhibiting TSLP<\/jats:styled-content>\u2010induced pulmonary immunopathology.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1476-5381.2012.02131.x","type":"journal-article","created":{"date-parts":[[2012,8,6]],"date-time":"2012-08-06T14:05:48Z","timestamp":1344261948000},"page":"363-374","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Selective inhibition by simvastatin of IRF<\/scp>3 phosphorylation and TSLP<\/scp> production in dsRNA<\/scp>\u2010challenged bronchial epithelial cells from COPD<\/scp> donors"],"prefix":"10.1111","volume":"168","author":[{"given":"Angelica","family":"Brandelius","sequence":"first","affiliation":[{"name":"Department of Experimental Medical Science Lund University Lund 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