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Basic fibroblast growth factor induces expression of the PDGF receptor-alpha on human bronchial smooth muscle cells
J C Bonner1, A Badgett, P M Lindroos
1Airway Inflammation Section, National Institute of Environmental Health Sciences, Research Triangle Park 27709, USA. Bonner_J@NIEHS.NIH.GOV
Abstract:
Bronchial smooth muscle cell (SMC) hyperplasia is a key feature in the pathology of asthma. Platelet-derived growth factor (PDGF) isoforms are SMC mitogens. We investigated the effect of basic fibroblast growth factor (bFGF), transforming growth factor-beta 1 (TGF-beta 1), interleukin-1 beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) on the PDGF receptor system on human bronchial SMC from three different donors. bFGF induced gene expression of the PDGF alpha-receptor (PDGF-R alpha) approximately threefold without altering the PDGF beta-receptor (PDGF-R beta). IL-1 beta and TNF-alpha did not affect the PDGF receptor system. TGF-beta 1 downregulated PDGF-R alpha mRNA approximately 60% without changing PDGF-R beta mRNA levels. Receptor assays showed that bFGF increased the [125I]PDGF-AA binding site approximately twofold, whereas TGF-beta 1 reduced [125I]PDGF-AA binding approximately 60%. TGF-beta 1, but not latent TGF-beta 1, counteracted the bFGF-induced increase in [125I]PDGF-AA binding. PDGF-AA-stimulated tyrosine phosphorylation on the PDGF-R alpha was enhanced after treatment with bFGF, bFGF pretreatment enhanced the mitogenic response of SMC to PDGF-AA and PDGF-AB. These findings suggest that upregulation of the PDGF-R alpha by bFGF could contribute to SMC hyperplasia during chronic airway inflammation in asthma.
Insights
Basic fibroblast growth factor (bFGF) upregulates the platelet-derived growth factor alpha-receptor (PDGF-R alpha) in airway smooth muscle cells. This suggests bFGF may contribute to airway hyperresponsiveness in asthma.
Area of Science:
- Cellular and Molecular Biology
- Respiratory Medicine
- Immunology
Background:
- Bronchial smooth muscle cell (SMC) hyperplasia is a critical pathological feature of asthma.
- Platelet-derived growth factor (PDGF) isoforms are known mitogens for SMCs.
- The role of growth factors in modulating the PDGF receptor system in airway SMCs requires further elucidation.
Purpose of the Study:
- To investigate the effects of basic fibroblast growth factor (bFGF), transforming growth factor-beta 1 (TGF-beta 1), interleukin-1 beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) on the PDGF receptor system in human bronchial SMCs.
- To determine how these factors influence PDGF receptor expression, binding, and downstream signaling.
- To assess the impact of these modulations on SMC mitogenesis.
Main Methods:
- Human bronchial SMCs from three donors were treated with bFGF, TGF-beta 1, IL-1 beta, and TNF-alpha.
- Gene expression of PDGF alpha-receptor (PDGF-R alpha) and PDGF beta-receptor (PDGF-R beta) was analyzed.
- Receptor binding assays ([125I]PDGF-AA) and PDGF-AA-stimulated tyrosine phosphorylation were performed.
- Mitogenic responses to PDGF-AA and PDGF-AB were assessed following growth factor pretreatment.
Main Results:
- bFGF significantly upregulated PDGF-R alpha gene expression and [125I]PDGF-AA binding sites, enhancing PDGF-AA-stimulated tyrosine phosphorylation.
- TGF-beta 1 downregulated PDGF-R alpha mRNA and [125I]PDGF-AA binding, counteracting the effect of bFGF.
- IL-1 beta and TNF-alpha had no significant effect on the PDGF receptor system.
- bFGF pretreatment enhanced the mitogenic response of SMCs to PDGF-AA and PDGF-AB.
Conclusions:
- Upregulation of PDGF-R alpha by bFGF in bronchial SMCs may contribute to SMC hyperplasia in asthma.
- TGF-beta 1 exerts an opposing effect by downregulating PDGF-R alpha.
- These findings highlight the complex interplay of growth factors in regulating airway smooth muscle proliferation and suggest potential therapeutic targets for asthma.