JC Bonner, A Badgett, PM Lindroos and AR Osornio-Vargas
Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.

Fibroblasts are the central target cell in pulmonary fibrotic diseases, and their proliferation is mediated largely by platelet-derived growth factor (PDGF) isoforms secreted by activated lung macrophages. Several other macrophage-derived cytokines that are increased during fibrogenesis, including interleukin-1 beta and transforming growth factor-beta 1 (TGF-beta 1), could potentially modulate the mitogenic and chemotactic activity of PDGF by altering the expression of cell- surface PDGF receptors on fibroblasts. The PDGF receptor system on fibroblasts from a variety of tissues shows heterogeneous responses to TGF-beta 1. Lung fibroblasts have not been investigated in this regard. TGF-beta 1 downregulated the gene expression of the 6.5 kb PDGF-alpha receptor (PDGF-R alpha) transcript in normal human lung fibroblasts in a concentration-dependent fashion that was maximal at 3 ng/ml TGF-beta 1; this corresponded with a decrease in cell-surface PDGF-R alpha as measured by radioligand binding assays using [125I]PDGF-AA. The TGF- beta 1-induced down-regulation of the PDGF-R alpha gene was rapid (maximal suppression by 2 h post-treatment) and preceded the decrease in cell-surface alpha-receptor (maximal reduction by 6 h post- treatment). TGF-beta 1 treatment did not alter the rate of PDGF-R alpha mRNA degradation following the inhibition of transcription using actinomycin D, indicating that TGF-beta 1 increases PDGF-R alpha transcription. Scatchard analysis of saturation binding data showed that TGF-beta 1 decreased the number of [125I]PDGF-AA binding sites 5- fold without affecting receptor affinity. [125I]PDGF-AB binding sites were downregulated approximately 25%, and the number of [125I]PDGF-BB binding sites was not changed by TGF-beta 1 treatment, indicating that the PDGF-beta receptor was not affected. TGF-beta 1 reduced the mitogenic and chemotactic response to PDGF-AA by > 90%, whereas these biologic response to PDGF-AB and PDGF-BB were inhibited 50% to 80%. The proliferative and chemotactic responses of fibroblasts during tissue remodeling or during lung fibrosis are likely controlled by a complex network involving PDGF isoforms and cytokines that modify the PDGF receptor system.

This article has been cited by other articles:

				B. C. Willis, J. M. Liebler, K. Luby-Phelps, A. G. Nicholson, E. D. Crandall, R. M. du Bois, and Z. Borok Induction of Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells by Transforming Growth Factor-{beta}1: Potential Role in Idiopathic Pulmonary Fibrosis Am. J. Pathol., May 1, 2005; 166(5): 1321 - 1332. [Abstract] [Full Text] [PDF]

				U. Bartram and C. P. Speer The Role of Transforming Growth Factor {beta} in Lung Development and Disease Chest, February 1, 2004; 125(2): 754 - 765. [Abstract] [Full Text] [PDF]

				J. Luo and M. W. Miller Platelet-Derived Growth Factor-Mediated Signal Transduction Underlying Astrocyte Proliferation: Site of Ethanol Action J. Neurosci., November 15, 1999; 19(22): 10014 - 10025. [Abstract] [Full Text] [PDF]

				C.-H. Heldin and B. Westermark Mechanism of Action and In Vivo Role of Platelet-Derived Growth Factor Physiol Rev, October 1, 1999; 79(4): 1283 - 1316. [Abstract] [Full Text] [PDF]

				J. E. Boyle, P. M. Lindroos, A. B. Rice, L. Zhang, D. C. Zeldin, and J. C. Bonner Prostaglandin-E2 Counteracts Interleukin-1beta -Stimulated Upregulation of Platelet-Derived Growth Factor alpha -Receptor on Rat Pulmonary Myofibroblasts Am. J. Respir. Cell Mol. Biol., March 1, 1999; 20(3): 433 - 440. [Abstract] [Full Text]

				A. Coste, J.-P. Lefaucheur, Q.-P. Wang, E. Lesprit, F. Poron, R. Peynegre, and E. Escudier Expression of the Transforming Growth Factor {beta} Isoforms in Inflammatory Cells of Nasal Polyps Arch Otolaryngol Head Neck Surg, December 1, 1998; 124(12): 1361 - 1366. [Abstract] [Full Text] [PDF]

				J. C. Bonner, P. M. Lindroos, A. B. Rice, C. R. Moomaw, and D. L. Morgan Induction of PDGF receptor-alpha in rat myofibroblasts during pulmonary fibrogenesis in vivo Am J Physiol Lung Cell Mol Physiol, January 1, 1998; 274(1): L72 - L80. [Abstract] [Full Text] [PDF]

				Y.-Z. Wang, P. Zhang, A. B. Rice, and J. C. Bonner Regulation of Interleukin-1beta -induced Platelet-derived Growth Factor Receptor-alpha Expression in Rat Pulmonary Myofibroblasts by p38 Mitogen-activated Protein Kinase J. Biol. Chem., July 14, 2000; 275(29): 22550 - 22557. [Abstract] [Full Text] [PDF]