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Published ahead of print on August 27, 2004, doi:10.1165/rcmb.2004-0182OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 31, pp. 679-686, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.2004-0182OC

Transforming Growth Factor–ß Antagonizes Alveolar Type II Cell Proliferation Induced by Keratinocyte Growth Factor

Feijie Zhang, Larry D. Nielsen, Joseph J. Lucas and Robert J. Mason

Departments of Medicine and Pediatrics, National Jewish Medical and Research Center, Denver, Colorado

Address correspondence to: Robert J. Mason, M.D., National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: masonb{at}njc.org

Keratinocyte growth factor (KGF) is a mitogen for rat type II cells and also stimulates differentiation in vitro. Administration of KGF also protects the lung from a variety of injuries and subsequent development of fibrosis. Because transforming growth factor (TGF)-ß has been shown to inhibit epithelial cell proliferation and surfactant protein gene expression in other systems and is thought to be a major effector in pulmonary fibrosis, we sought to determine if TGF-ß would antagonize the effects of KGF in primary cultures of alveolar type II cells. Type II cells were cultured on a matrix of type I collagen and Matrigel in the presence or absence of KGF and/or TGF-ß. KGF alone greatly stimulated proliferation and increased cyclin-dependent kinase (cdk) 2 kinase activity and Retinoblastoma susceptibility gene product (Rb) phosphorylation. Cyclin D1, cdk2, and cdc25A protein levels were increased, and p15Ink4b and p27Kip1 protein levels were decreased. TGF-ß markedly inhibited alveolar epithelial cell proliferation induced by KGF. TGF-ß inhibited cdk2 enzyme activity and Rb phosphorylation and increased p15Ink4b protein levels. TGF-ß also inhibited differentiation induced by KGF as measured by secretion of surfactant protein–A into the apical media. In summary, TGF-ß inhibits the proliferative effect of KGF in vitro and may be a biologic antagonist of KGF.

Abbreviations: Dulbecco's modified Eagle's medium, DMEM • dithiothreitol, DTT • horseradish peroxidase, HRP • immunoglobulin, Ig • immunoprecipitation, IP • keratinocyte growth factor, KGF • polyacrylamide gel electrophoresis, PAGE • phosphate-buffered saline, PBS • Retinoblastoma susceptibility gene product, Rb • real-time polymerase chain reaction, RT-PCR • sodium dodecyl sulfate, SDS • transforming growth factor, TGF




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