title: PDGF-D expression is down-regulated by TGFβ in fibroblasts.
abstract: Transforming growth factor-β (TGFβ) is a key mediator of fibrogenesis. TGFβ is overexpressed and activated in fibrotic diseases, regulates fibroblast differentiation into myofibroblasts and induces extracellular matrix deposition. Platelet-derived growth factor (PDGF) is also a regulator of fibrogenesis. Some studies showed a link between TGFβ and PDGF in certain fibrotic diseases. TGFβ induces PDGF receptor alpha expression in scleroderma fibroblasts. PDGF-C and -D are the most recently discovered ligands and also play a role in fibrosis. In this study, we report the first link between TGFβ and PDGF-D and -C ligands. In normal fibroblasts, TGFβ down-regulated PDGF-D expression and up-regulated PDGF-C expression at the mRNA and protein levels. This phenomenon is not limited to TGFβ since other growth factors implicated in fibrosis, such as FGF, EGF and PDGF-B, also regulated PDGF-D and PDGF-C expression. Among different kinase inhibitors, only TGFβ receptor inhibitors and the IκB kinase (IKK) inhibitor BMS-345541 blocked the effect of TGFβ. However, activation of the classical NF-κB pathway was not involved. Interestingly, in a model of lung fibrosis induced by either bleomycin or silica, PDGF-D was down-regulated, which correlates with the production of TGFβ and other fibrotic growth factors. In conclusion, the down-regulation of PDGF-D by TGFβ and other growth factors may serve as a negative feedback in the network of cytokines that control fibrosis.
authors.affiliation: de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Saima
authors.initials: S
authors.lastname: Charni Chaabane
authors.affiliation: de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Coomans de Brachène
authors.affiliation: de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Essaghir
authors.affiliation: de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Amélie
authors.initials: A
authors.lastname: Velghe
authors.affiliation: Louvain center of Toxicology and Applied Pharmacology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lo Re
authors.affiliation: de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Stockis
authors.affiliation: de Duve Institute, Université catholique de Louvain, Brussels, Belgium; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wallonia, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lucas
authors.affiliation: Center of Vascular Research, University of New South Wales, Sydney, Australia.
authors.forename: Levon M
authors.initials: LM
authors.lastname: Khachigian
authors.affiliation: Louvain center of Toxicology and Applied Pharmacology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Huaux
authors.affiliation: de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Demoulin
mesh_terms: D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D052816:Foreskin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D008222:Lymphokines; C427493:PDGFD protein, human; D010982:Platelet-Derived Growth Factor; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C411423:platelet-derived growth factor C