Background: COPD is a progressive chronic lung disease characterized by pulmonary inflammation. Several recent studies indicate aberrant expression of WNT ligands and Frizzled receptors in the disease. For example, WNT-5A/B ligand expression was recently found increased in lung fibroblasts of COPD patients. However, possible effects of WNT-5A and WNT-5B on inflammation have not been investigated yet. In this study we assessed the regulation of inflammatory cytokine release in response to WNT-5A/B signalling in human lung fibroblasts. Methods: Primary human fetal lung fibroblasts (MRC-5), and primary lung fibroblasts from COPD patients and non-COPD controls were treated with recombinant WNT-5A or WNT-5B to assess IL-6 and CXCL8 cytokine secretion and gene expression levels. Results: Following WNT-5B, and to a lesser extent WNT-5A stimulation, fibroblasts showed increased IL-6 and CXCL8 cytokine secretion and mRNA expression. WNT-5B-mediated IL-6 and CXCL8 release was higher in fibroblasts from COPD patients than in non-COPD controls. In MRC-5 fibroblasts, WNT-5B-induced CXCL8 release was mediated primarily via the Frizzled-2 receptor and TAK1-signalling, whereas canonical β-catenin signalling was not involved. In further support of non-canonical signalling, activation of JNK, p38 and p65 NF-κB by WNT-5B was shown. Furthermore, inhibition of JNK and p38 prevented WNT-5B-induced IL-6 and CXCL8 secretion, whereas IKK inhibition prevented CXCL8 secretion only, indicating distinct pathways for WNT-5B-induced IL-6 and CXCL8 release. Conclusion: WNT-5B induces IL-6 and CXCL8 secretion in human lung fibroblasts via Frizzled-2 and TAK1-mediated signalling. As WNT-5 signalling is increased in COPD, this WNT-5-induced inflammatory response could represent a therapeutic target.
- Copyright © 2015, American Journal of Physiology - Lung Cellular and Molecular Physiology