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

Abstract

BACKGROUND AND PURPOSEStatin 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 APPROACHEpithelial 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 mg·mL ) before dsRNA. Cytokine expression and production, and transcription factor (IRF3 and NF-kB) activation were determined. KEY RESULTSdsRNA induced TSLP, TNF-a, CXCL8 and IFN-b. 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-kB activation nor did it reduce production of TNF-a and CXCL8. Instead, simvastatin inhibited dsRNA-induced IRF3 phosphorylation and generation of IFN-b. CONCLUSIONS AND IMPLICATIONSIndependent of mevalonate and NF-kB, previously acknowledged anti-inflammatory mechanisms of pleiotropic statins, simvastatin selectively inhibited dsRNA-induced IRF3 activation and production of TSLP and IFN-b 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. AbbreviationsCOPD, chronic obstructive pulmonary disease; DAMP, danger-associated molecular patterns; dsRNA, double stranded RNA; GOLD, global initiative for obstructive lung disease; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; IKK, IkB kinase; IRF3, IFN regulatory factor 3; RV, rhinoviral; TANK, TRAF family member-associated NF-kB activator; TBK-1, TANK-binding kinase-1; Th, T helper cells; TLR3, Toll receptor 3; TRPV1, transient receptor potential cation channel subfamily V member 1; TSLP, thymic stromal lymphopoietin; UBC, Ubiquitin C

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

“…Simvastatin can selectively inhibit dsRNA-induced IRF3 activation and production of TSLP and IFNβ in these epithelial cells (Brandelius, et al, 2013). Because viral infections are thought to be one mechanism that induces acute exacerbations in asthma and COPD, statins may serve to mitigate exacerbations by this mechanism.…”

Statins attenuate antiviral IFN-β and ISG expression via inhibiting IRF3/JAK/STAT signaling in poly(I:C)-treated hyperlipidemic mice and macrophages

“…Hyperlipidemic mice exhibit altered immune responses (23,24,33). Atorvastatin improved plaque stability in ApoE-knockout mice (39), and exerted hypolipidemic and anti-inflammatory action in ApoE/LDL receptor-knockout mice (40). However, to our knowledge, the effects of statins on the antiviral immune response in hyperlipidemic mice have not been evaluated.…”

“…7a, b), indicating that the negative effect of statins on the antiviral immune response occurs through the inhibition of IRF3-mediated JAK/STAT signaling in macrophages. In bronchial epithelial cells, simvastatin impairs dsRNA-induced IRF3 activation and IFN-β production, producing an antiinflammatory effect (40). Therefore, statins may inhibit the IRF3-mediated JAK/STAT signaling pathway in multiple cell types.…”

Impact of respiratory viruses on the course of chronic obstructive pulmonary disease: Towards optimizing treatment

“…В культурах бронхиальных эпителиальных клеток двуспиральная РНК инду-цировала большую экспрессию мРНК TSLP и продукцию соот-ветствующего белкового продукта у больных ХОБЛ в сравнении с аналогичными культурами, изолированными у клинически здо-ровых курящих лиц. Установлено, что статины, в частности сим-вастатин, подавляют индуцированную вирусами продукцию TSLP респираторными эпителиоцитами [42]. Это и ретроспек-тивные данные о способности статинов снижать летальность и частоту госпитализаций у больных ХОБЛ [43] подтверждают ги-потезу об участии TSLP в патогенезе ассоциированных с ОРВИ обострений и определяют перспективное направление поиска средств предотвращения и снижения тяжести индуцированных вирусами эпизодов усугубления респираторных симптомов ХОБЛ.…”