title: Fibroblast growth factor 2 and transforming growth factor beta1 synergism in human bronchial smooth muscle cell proliferation.
abstract: Bronchial smooth muscle cell (BSMC) hyperplasia is a typical feature of airway remodeling and contributes to airway obstruction and hyperresponsiveness in asthma. Fibroblast growth factor 2 (FGF-2) and transforming growth factor beta1 (TGF-beta1) are sequentially upregulated in asthmatic airways after allergic challenge. Whereas FGF-2 induces BSMC proliferation, the mitogenic effect of TGF-beta1 remains controversial, and the effect of sequential FGF-2 and TGF-beta1 co-stimulation on BSMC proliferation is unknown. This study aimed to assess the individual and sequential cooperative effects of FGF-2 and TGF-beta1 on human BSMC proliferation and define the underlying mechanisms. Mitogenic response was measured using crystal violet staining and [3H]-thymidine incorporation. Steady-state mRNA and protein levels were measured by semiquantitative RT-PCR, Western blot, and ELISA, respectively. TGF-beta1 (0.1-20 ng/ml) alone had no effect on BSMC proliferation, but increased the proliferative effect of FGF-2 (2 ng/ml) in a concentration-dependent manner (up to 6-fold). Two distinct platelet-derived growth factor receptor (PDGFR) inhibitors, AG1296 and Inhibitor III, as well as a neutralizing Ab against PDGFRalpha, partially blocked the synergism between these two growth factors. In this regard, TGF-beta1 increased PDGF-A and PDGF-C mRNA expression as well as PDGF-AA protein expression. Moreover, FGF-2 pretreatment increased the mRNA and protein expression of PDGFRalpha and the proliferative effect of exogenous PDGF-AA (140%). Our data suggest that FGF-2 and TGF-beta1 synergize in BSMC proliferation and that this synergism is partially mediated by a PDGF loop, where FGF-2 and TGF-beta1 upregulate the receptor (PDGFRalpha) and the ligands (PDGF-AA and PDGF-CC), respectively. This powerful synergistic effect may thus contribute to the hyperplastic phenotype of BSMC in remodeled asthmatic airways.
authors.affiliation: Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Canada.
authors.forename: Ynuk
authors.initials: Y
authors.lastname: Bossé
authors.forename: Charles
authors.initials: C
authors.lastname: Thompson
authors.forename: Jana
authors.initials: J
authors.lastname: Stankova
authors.forename: Marek
authors.initials: M
authors.lastname: Rola-Pleszczynski
mesh_terms: D000328:Adult; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007223:Infant; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D020032:Tyrphostins; C075278:platelet-derived growth factor A; C411423:platelet-derived growth factor C; D016222:Fibroblast Growth Factor 2; C106250:6,7-dimethoxy-3-phenylquinoxaline; D004247:DNA; D020796:Receptor, Platelet-Derived Growth Factor alpha; D010959:Tissue Plasminogen Activator