title: WNT-5A regulates TGF-β-related activities in liver fibrosis.
abstract: WNT-5A is a secreted growth factor that belongs to the noncanonical members of the Wingless-related MMTV-integration family. Previous studies pointed to a connection between WNT-5A and the fibrogenic factor TGF-β warranting further studies into the functional role of WNT-5A in liver fibrosis. Therefore, we studied WNT-5A expressions in mouse and human fibrotic livers and examined the relation between WNT-5A and various fibrosis-associated growth factors, cytokines, and extracellular matrix proteins. WNT-5A gene and protein expressions were significantly increased in fibrotic mouse and human livers compared with healthy livers. Regression or therapeutic intervention in mice resulted in decreased hepatic WNT-5A levels paralleled by lower collagen levels. Immunohistochemical analysis showed WNT-5A staining in fibrotic septa colocalizing with desmin staining indicating WNT-5A expression in myofibroblasts. In vitro studies confirmed WNT-5A expression in this cell type and showed that TGF-β significantly enhanced WNT-5A expression in contrast to PDGF-BB and proinflammatory cytokines IL-1β and TNF-α. Additionally, TGF-β induces the expression of the WNT receptors FZD2 and FZD8. After silencing of WNT-5A, reduced levels of collagen type I, vimentin, and fibronectin in TGF-β-stimulated myofibroblasts were measured compared with nonsilencing siRNA-treated controls. Interestingly, the antifibrotic cytokine IFNγ suppressed WNT-5A in vitro and in vivo. IFNγ-treated fibrotic mice showed significantly less WNT-5A expression compared with untreated fibrotic mice. In conclusion, WNT-5A paralleled collagen I levels in fibrotic mouse and human livers. WNT-5A expression in myofibroblasts is induced by the profibrotic factor TGF-β and plays an important role in TGF-β-induced regulation of fibrotic matrix proteins, whereas its expression can be reversed upon treatment, both in vitro and in vivo.NEW & NOTEWORTHYThis study describes the localization and functional role of WNT-5A in human and mouse fibrotic livers. Hepatic WNT-5A expression parallels collagen type I expression. In vivo and in vitro, the myofibroblasts were identified as the key hepatic cells producing WNT-5A. WNT-5A is under control of TGF-β and its activities are primarily profibrotic.
authors.affiliation: Department of Pharmacokinetics, Toxicology and Targeting. Groningen Research Institute for Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands; and e.beljaars@rug.nl.
authors.forename: Leonie
authors.initials: L
authors.lastname: Beljaars
authors.affiliation: Department of Pharmacokinetics, Toxicology and Targeting. Groningen Research Institute for Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands; and.
authors.forename: Sara
authors.initials: S
authors.lastname: Daliri
authors.affiliation: Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands.
authors.forename: Christa
authors.initials: C
authors.lastname: Dijkhuizen
authors.affiliation: Department of Pharmacokinetics, Toxicology and Targeting. Groningen Research Institute for Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands; and.
authors.forename: Klaas
authors.initials: K
authors.lastname: Poelstra
authors.affiliation: Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands.
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
mesh_terms: D000818:Animals; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000071818:Wnt-5a Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D003893:Desmin; D053583:Interleukin-1beta; D016212:Transforming Growth Factor beta; D000071818:Wnt-5a Protein; D007371:Interferon-gamma; D003094:Collagen
keywords: WNT; fibrosis; interferon γ; remodeling; transforming growth factor-β