TGF‐β‐induced profibrotic signaling is regulated in part by the WNT receptor Frizzled‐8
2016; Wiley; Volume: 30; Issue: 5 Linguagem: Inglês
10.1096/fj.201500129
ISSN1530-6860
AutoresAnita I. R. Spanjer, Hoeke A. Baarsma, Lisette M. Oostenbrink, Sepp R. Jansen, Christine C. Kuipers, Michael Lindner, Dirkje S. Postma, Herman Meurs, Irene H. Heijink, Reinoud Gosens, Mélanie Königshoff,
Tópico(s)Neonatal Respiratory Health Research
ResumoThe FASEB JournalVolume 30, Issue 5 p. 1823-1835 Research CommunicationFree to Read TGF-β-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8 Anita I. R. Spanjer, Anita I. R. Spanjer Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorHoeke A. Baarsma, Hoeke A. Baarsma Comprehensive Pneumology Center, Helmholtz Center Munich, German Center for Lung Research (DZL), University Hospital Grosshadern, Ludwig Maximilians University Munich, Munich, GermanySearch for more papers by this authorLisette M. Oostenbrink, Lisette M. Oostenbrink Comprehensive Pneumology Center, Helmholtz Center Munich, German Center for Lung Research (DZL), University Hospital Grosshadern, Ludwig Maximilians University Munich, Munich, GermanySearch for more papers by this authorSepp R. Jansen, Sepp R. Jansen Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorChristine C. Kuipers, Christine C. Kuipers Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorMichael Lindner, Michael Lindner Asklepios Fachkliniken Munchen-Gauting, Munich, GermanySearch for more papers by this authorDirkje S. Postma, Dirkje S. Postma Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorHerman Meurs, Herman Meurs Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorIrene H. Heijink, Irene H. Heijink Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorReinoud Gosens, Corresponding Author Reinoud Gosens r.gosens@rug.nl Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsThese authors contributed equally to this work. Correspondence: Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: r.gosens@rug.nl Correspondence: Max Lebsche Platz 31, 81377 München, Germany. E-mail: melanie.koenigshoff@hemholtz-muenchen.deSearch for more papers by this authorMelanie Königshoff, Corresponding Author Melanie Königshoff melanie.koenigshoff@hemholtz-muenchen.de Comprehensive Pneumology Center, Helmholtz Center Munich, German Center for Lung Research (DZL), University Hospital Grosshadern, Ludwig Maximilians University Munich, Munich, GermanyThese authors contributed equally to this work. Correspondence: Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: r.gosens@rug.nl Correspondence: Max Lebsche Platz 31, 81377 München, Germany. E-mail: melanie.koenigshoff@hemholtz-muenchen.deSearch for more papers by this author Anita I. R. Spanjer, Anita I. R. Spanjer Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorHoeke A. Baarsma, Hoeke A. Baarsma Comprehensive Pneumology Center, Helmholtz Center Munich, German Center for Lung Research (DZL), University Hospital Grosshadern, Ludwig Maximilians University Munich, Munich, GermanySearch for more papers by this authorLisette M. Oostenbrink, Lisette M. Oostenbrink Comprehensive Pneumology Center, Helmholtz Center Munich, German Center for Lung Research (DZL), University Hospital Grosshadern, Ludwig Maximilians University Munich, Munich, GermanySearch for more papers by this authorSepp R. Jansen, Sepp R. Jansen Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorChristine C. Kuipers, Christine C. Kuipers Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorMichael Lindner, Michael Lindner Asklepios Fachkliniken Munchen-Gauting, Munich, GermanySearch for more papers by this authorDirkje S. Postma, Dirkje S. Postma Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorHerman Meurs, Herman Meurs Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorIrene H. Heijink, Irene H. Heijink Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsSearch for more papers by this authorReinoud Gosens, Corresponding Author Reinoud Gosens r.gosens@rug.nl Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsThese authors contributed equally to this work. Correspondence: Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: r.gosens@rug.nl Correspondence: Max Lebsche Platz 31, 81377 München, Germany. E-mail: melanie.koenigshoff@hemholtz-muenchen.deSearch for more papers by this authorMelanie Königshoff, Corresponding Author Melanie Königshoff melanie.koenigshoff@hemholtz-muenchen.de Comprehensive Pneumology Center, Helmholtz Center Munich, German Center for Lung Research (DZL), University Hospital Grosshadern, Ludwig Maximilians University Munich, Munich, GermanyThese authors contributed equally to this work. Correspondence: Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: r.gosens@rug.nl Correspondence: Max Lebsche Platz 31, 81377 München, Germany. E-mail: melanie.koenigshoff@hemholtz-muenchen.deSearch for more papers by this author First published: 05 February 2016 https://doi.org/10.1096/fj.201500129Citations: 4 This article includes supplemental data. Please visit http://www.fasebj.org to obtain this information. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract TGF-β is important in lung injury and remodeling processes. TGF-β and Wingless/integrase-1 (WNT) signaling are interconnected; however, the WNT ligand-receptor complexes involved are unknown. Thus, we aimed to identify Frizzled (FZD) receptors that mediate TGF-β-induced profibrotic signaling. MRC-5 and primary human lung fibroblasts were stimulated with TGF-β1, WNT-5A, or WNT-5B in the presence and absence of specific pathway inhibitors. Specific small interfering RNA was used to knock down FZD8. In vivo studies using bleomycin-induced lung fibrosis were performed in wild-type and FZD8-deficient mice. TGF-β 1 induced FZD8 specifically via Smad3-dependent signaling in MRC-5 and primary human lung fibroblasts. It is noteworthy that FZD8 knockdown reduced TGF-β1-induced collagen Iα1, fibronectin, versican, α-smooth muscle (sm)-actin, and connective tissue growth factor. Moreover, bleomycin-induced lung fibrosis was attenuated in FZD8-deficient mice in vivo. Although inhibition of canonical WNT signaling did not affect TGF-β 1-induced gene expression in vitro, noncanonical WNT-5B mimicked TGF-β1-induced fibroblast activation. FZD8 knockdown reduced both WNT-5B-induced gene expression of fibronectin and α-sm-actin, as well as WNT-5B-induced changes in cellular impedance. Collectively, our findings demonstrate a role for FZD8 in TGF-β-induced profibrotic signaling and imply that WNT-5B may be the ligand for FZD8 in these responses.—Spanjer, A. I. R., Baarsma, H. A., Oostenbrink, L. M., Jansen, S. R., Kuipers, C. C., Lindner, M., Postma, D. S., Meurs, H., Heijink, I. H., Gosens, R., Königshoff, M. TGF-β-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8. FASEB J. 30, 1823–1835 (2016). www.fasebj.org Citing Literature Supporting Information Filename Description fsb2030005014-sup-0001.docapplication/doc, 38 KB Supplementary Material fsb2030005014-sup-0002.pdfPDF document, 3.6 MB Supplementary Material fsb2030005014-sup-0003.pdfPDF document, 1.2 MB Supplementary Material Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. 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