Role of aberrant WNT signalling in the airway epithelial response to cigarette smoke in chronic obstructive pulmonary disease
- Irene H Heijink1,2,3,
- Harold G de Bruin1,
- Maarten van den Berge2,3,
- Lisa J C Bennink1,2,
- Simone M Brandenburg1,
- Reinoud Gosens3,4,
- Antoon J van Oosterhout1,3,
- Dirkje S Postma2,3
- 1Department of Pathology and Medical Biology, Lab of Allergology and Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- 2Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- 3GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- 4Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands
- Correspondence to Dr Irene H Heijink, Pathology and Medical Biology, Lab of Allergology and Pulmonary Diseases, University of Groningen, EA52, University Medical Center Groningen, Hanzeplein 1, Groningen NL-9713 GZ, The Netherlands; h.i.heijink{at}umcg.nl
- Received 24 January 2012
- Revised 9 January 2013
- Accepted 10 January 2013
- Published Online First 31 January 2013
Abstract
Background WNT signalling is activated during lung tissue damage and inflammation. We investigated whether lung epithelial expression of WNT ligands, receptors (frizzled; FZD) or target genes is dysregulated on cigarette smoking and/or in chronic obstructive pulmonary disease (COPD).
Methods We studied this in human lung epithelial cell lines and primary bronchial epithelial cells (PBEC) from COPD patients and control (non-)smokers, at baseline and on cigarette smoke extract (CSE) exposure.
Results CSE significantly decreased WNT-4, WNT-10B and FZD2 and increased WNT-5B mRNA expression in 16HBE, but did not affect WNT-4 protein. The mRNA expression of WNT-4, but not other WNT ligands, was lower in PBEC from smokers than non-smokers and downregulated by CSE in PBEC from all groups, yet higher in PBEC from COPD patients than control smokers. Moreover, PBEC from COPD patients displayed higher WNT-4 protein expression than both smokers and non-smokers. Exogenously added WNT-4 significantly increased CXCL8/IL-8, IL-6, CCL5/RANTES, CCL2/MCP-1 and vascular endothelial growth factor (VEGF) secretion in 16HBE, but did not affect the canonical WNT target genes MMP-2, MMP-9, fibronectin, β-catenin, Dickkopf and axin-2, and induced activation of the non-canonical signalling molecule p38. Moreover, WNT-4 potentiated the CSE-induced upregulation of IL-8 and VEGF.
Conclusions WNT-4 mRNA and protein levels are higher in PBEC from COPD patients than control (non-)smokers, while cigarette smoke downregulates airway epithelial WNT-4 mRNA, but not protein expression. As WNT-4 further increases CSE-induced pro-inflammatory cytokine release in bronchial epithelium, we propose that higher epithelial WNT-4 levels in combination with cigarette smoking may have important implications for the development of airway inflammation in COPD.
