Advanced

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

Brandelius, Angelica LU ; Mahmutovic Persson, Irma LU ; Calvén, Jenny LU ; Bjermer, Leif LU ; Persson, Carl LU ; Andersson, Morgan LU and Uller, Lena LU (2012) In British Journal of Pharmacology
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
British Journal of Pharmacology
publisher
The British Pharmacological Society
external identifiers
  • WOS:000313751200009
  • PMID:22881993
  • Scopus:84871585883
ISSN
1476-5381
DOI
10.1111/j.1476-5381.2012.02131.x
language
English
LU publication?
yes
id
e3ce2b93-a6da-4e08-b9d4-29af1f990d02 (old id 3047645)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22881993?dopt=Abstract
date added to LUP
2012-09-05 19:07:48
date last changed
2016-10-13 04:27:43
@misc{e3ce2b93-a6da-4e08-b9d4-29af1f990d02,
  abstract     = {Background and purpose: <br/><br>
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. <br/><br>
<br/><br>
Experimental approach: <br/><br>
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. <br/><br>
<br/><br>
Key results: <br/><br>
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. <br/><br>
<br/><br>
Conclusions and implications: <br/><br>
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.},
  author       = {Brandelius, Angelica and Mahmutovic Persson, Irma and Calvén, Jenny and Bjermer, Leif and Persson, Carl and Andersson, Morgan and Uller, Lena},
  issn         = {1476-5381},
  language     = {eng},
  month        = {08},
  publisher    = {ARRAY(0x95cf728)},
  series       = {British Journal of Pharmacology},
  title        = {Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors.},
  url          = {http://dx.doi.org/10.1111/j.1476-5381.2012.02131.x},
  year         = {2012},
}