| 1. |
- Brandelius, Angelica, et al.
(author)
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Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors.
- 2012
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In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188.
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Journal article (peer-reviewed)abstract
- 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 our hypothesis that simvastatin may inhibit 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 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) ) prior to dsRNA. Cytokine expression and production, and transcription factor (IRF3 and NF-κB) activation were determined. Key results: dsRNA induced TSLP, TNFα, CXCL8, and IFNβ. TSLP was overproduced in dsRNA-exposed COPD cells compared to control. Simvastatin, concentration-dependently, but not dexamethasone, inhibited dsRNA-induced TSLP. Unexpectedly, simvastatin acted independent of mevalonate and did not affect dsRNA-induced NF-κB activation nor did it reduce production of TNFα and CXCL8. Instead, simvastatin inhibited dsRNA-induced IRF3 phosphorylation and generation of IFNβ. 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 IFNβ 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.
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| 2. |
- Calvén, Jenny, et al.
(author)
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Viral Stimuli Trigger Exaggerated Thymic Stromal Lymphopoietin Expression by Chronic Obstructive Pulmonary Disease Epithelium: Role of Endosomal TLR3 and Cytosolic RIG-I-Like Helicases.
- 2012
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In: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 4, s. 86-99
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Journal article (peer-reviewed)abstract
- Background: Rhinovirus (RV)-induced chronic obstructive pulmonary disease (COPD) exacerbations exhibit TH(2)-like inflammation. We hypothesized that RV-infected bronchial epithelial cells (BEC) overproduce TH(2)-switching hub cytokine, thymic stromal lymphopoietin (TSLP) in COPD. Methods: Primary BEC from healthy (HBEC) and from COPD donors (COPD-BEC) were grown in 12-well plates, infected with RV16 (0.5-5 MOI) or stimulated with agonists for either toll-like receptor (TLR) 3 (dsRNA, 0.1-10 μg/ml) or RIG-I-like helicases (dsRNA-LyoVec, 0.1-10 μg/ml). Cytokine mRNA and protein were determined (RTqPCR; ELISA). Results: dsRNA dose-dependently evoked cytokine gene overproduction of TSLP, CXCL8 and TNF-α in COPD-BEC compared to HBEC. This was confirmed using RV16 infection. IFN-β induction did not differ between COPD-BEC and HBEC. Endosomal TLR3 inhibition by chloroquine dose-dependently inhibited dsRNA-induced TSLP generation and reduced generation of CXCL8, TNF-α, and IFN-β. Stimulation of cytosolic viral sensors (RIG-I-like helicases) with dsRNA-LyoVec increased production of CXCL8, TNF-α, and IFN-β, but not TSLP. Conclusions: Endosomal TLR3-stimulation, by dsRNA or RV16, induces overproduction of TSLP in COPD-BEC. dsRNA- and RV-induced overproduction of TNF-α and CXCL8 involves endosomal TLR3 and cytosolic RIG-I-like helicases and so does the generation of IFN-β in COPD-BEC. RV16 and dsRNA-induced epithelial TSLP may contribute to pathogenic effects at exacerbations and development of COPD.
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| 3. |
- Mahmutovic Persson, Irma, et al.
(author)
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Capacity of capsazepinoids to relax human small airways and inhibit TLR3-induced TSLP and IFNβ production in diseased bronchial epithelial cells.
- 2012
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In: International Immunopharmacology. - : Elsevier BV. - 1878-1705 .- 1567-5769. ; 13:3, s. 292-300
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Journal article (peer-reviewed)abstract
- Thymic stromal lymphopoietin (TSLP), an immunomodulating potentially disease-inducing cytokine, is overproduced in TLR3-stimulated bronchial epithelial cells from asthmatic donors whereas production of antiviral IFNβ is deficient. It is of therapeutic interest that capsazepine inhibits epithelial TSLP and relaxes human small airways with similar potencies. However, it is not known if other capsazepine-like compounds share such dual actions. This study explores epithelial anti-TSLP and anti-IFNβ effects of capsazepine and novel capsazepine-like bronchorelaxants. We used primary bronchial epithelial cells from asthmatic and chronic obstructive pulmonary disease (COPD) donors, and human small airways dissected from surgically removed lungs. Seven novel capsazepinoids were about 10 times, and one compound (RES187) >30 times, more potent than capsazepine as relaxants of LTD(4)-contracted small airways. TLR3-induced TSLP, TNFα, CXCL8, and IFNβ mRNA and protein levels were dose-dependently and non-selectively inhibited by capsazepine, equally in cells from asthmatic and COPD donors. The novel compounds, except RES187, reduced TSLP and IFNβ but none are more potent than capsazepine. Only capsazepine consistently inhibited TNFα and CXCL8 production and attenuated TLR3-induced epithelial NF-κB signalling. Hence, the present compounds did not separate between inhibition of TLR3-induced epithelial TSLP and IFNβ, but all compounds, except capsazepine, did separate between the bronchorelaxant and the epithelial immune effects. We conclude that similar mechanisms may be involved in capsazepine-like inhibition of TLR3-induced epithelial TSLP and IFNβ and that these are distinct from mechanisms involved in relaxation of small airways by these compounds.
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