title: Noncanonical WNT-5B signaling induces inflammatory responses in human lung fibroblasts.
abstract: 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 to be 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 signaling in human lung fibroblasts. 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. 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 signaling, whereas canonical β-catenin signaling was not involved. In further support of noncanonical signaling, we showed activation of JNK, p38, and p65 NF-κB by WNT-5B. 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. WNT-5B induces IL-6 and CXCL8 secretion in pulmonary fibroblasts. In summary, WNT-5B mediates this via Frizzled-2 and TAK1. As WNT-5 signaling is increased in COPD, this WNT-5-induced inflammatory response could represent a therapeutic target.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center, Groningen, University of Groningen, Groningen, the Netherlands e.m.van.dijk@rug.nl.
authors.forename: Eline M
authors.initials: EM
authors.lastname: van Dijk
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center, Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Menzen
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center, Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Anita I R
authors.initials: AI
authors.lastname: Spanjer
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center, Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Laurens D C
authors.initials: LD
authors.lastname: Middag
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, Groningen, the Netherlands; and Groningen Research Institute for Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center, Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Corry-Anke A
authors.initials: CA
authors.lastname: Brandsma
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center, Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
mesh_terms: D016022:Case-Control Studies; D002460:Cell Line; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism*; D051157:Frizzled Receptors / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C508606:CXCL8 protein, human; C489742:FZD2 protein, human; D051157:Frizzled Receptors; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; C435831:WNT5B protein, human; D051153:Wnt Proteins
keywords: Frizzled-2; TAK1; chronic obstructive pulmonary disease