British journal of pharmacology · 2013
Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors.
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Brandelius Angelica, Mahmutovic Persson Irma, Calvén Jenny, Bjermer Leif, Persson Carl G A, Andersson Morgan, Uller Lena
Аннотация
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.
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.