WNT-4 regulates pro-inflammatory responses driven by epithelial-mesenchymal cross-talk

Introduction Epithelial-fibroblast communication is a key aspect of inflammation and remodelling in COPD. We previously showed that epithelial cells drive fibroblast-induced inflammation when co-cultured. The WNT signalling pathway ligands WNT-4 and -7B are predominantly expressed in epithelial cells, while WNT-5A and -5B are mostly expressed in fibroblasts. Aim We investigated whether WNT ligands are involved in pro-inflammatory responses that are induced in fibroblasts upon co-culture with epithelial cells. Methods We studied inflammatory cytokine and WNT mRNA expression after co-culturing primary airway fibroblasts of COPD grade IV patients with differentiated primary airway epithelial cells of healthy donors. Functional WNT effects were investigated in MRC-5 human lung fibroblasts co-cultured with differentiated primary airway epithelial cells. Results Co-culturing primary airway fibroblasts with differentiated airway epithelial cells did not change fibroblast WNT-5A and -5B mRNA expression, but increased epithelial WNT-4 and -7B mRNA expression. This was accompanied by increased interleukin (IL)-6 secretion, and an even stronger effect for the chemokine ligand CXCL8. Interestingly, WNT-4 stimulation reduced IL-6 and CXCL8 mRNA expression in MRC-5 fibroblasts, while WNT-7B, -5A and -5B caused an increase. Anti-WNT-4 increased IL-6, but not CXCL8 levels in a co-culture of MRC-5 fibroblasts with differentiated airway epithelial cells, whereas anti-WNT-7B, -WNT-5A and -WNT-5B had no effect. Conclusion These data show a regulatory role for epithelial-derived WNT-4 on IL-6 production that is induced upon co-culturing epithelial cells with fibroblasts. This process may contribute to inflammation in COPD.