GM-CSF increases airway smooth muscle cell connective tissue expression by inducing TGF-beta receptors.
Fibrosis around the smooth muscle of asthmatic airway walls leads to irreversible airway obstruction. Bronchial epithelial cells release granulocyte/macrophage colony-stimulating factor (GM-CSF) in asthmatics and are in close proximity to airway smooth muscle cells (ASMC). The findings in this study demonstrate that GM-CSF induces confluent, prolonged, serum-deprived cultures of ASMC to increase expression of collagen I and fibronectin. GM-CSF also induced ASMC to increase the expression of transforming growth factor (TGF)-beta receptors type I, II, and III (TbetaR-I, TbetaR-II, TbetaR-III), but had no detectable effect on the release of TGF-beta1 by the same ASMC. The presence of GM-CSF also induced the association of TGF-beta1 with TbetaR-III, which enhances binding of TGF-beta1 to TbetaR-II. The induction of TbetaRs was parallel to the increased induction of phosphorylated Smad2 (pSmad2) and connective tissue growth factor (CTGF), indicative of TGF-beta-mediated connective tissue synthesis. Dexamethasone decreased GM-CSF-induced TbetaR-I, TbetaR-II, TbetaR-III, pSmad2, CTGF, collagen I, and fibronectin. In conclusion, GM-CSF increases the responsiveness of ASMC to TGF-beta1-mediated connective tissue expression by induction of TbetaRs, which is inhibited by corticosteroids.
Chen
Gang
G
Department of Medicine, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Vancouver, British Columbia V6Z 3Z6, Canada.
Grotendorst
Gary
G
Eichholtz
Thomas
T
Khalil
Nasreen
N
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D003238:Connective Tissue / Q000378:metabolism*; D055513:Connective Tissue Growth Factor; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051899:Smad2 Protein; D014132:Trachea / Q000166:cytology; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D024042:Collagen Type I; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D005353:Fibronectins; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; C071736:betaglycan; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor