Published ahead of print on August 27, 2004, doi:10.1165/rcmb.2004-0182OC
© 2004 American Thoracic Society DOI: 10.1165/rcmb.2004-0182OC Transforming Growth Factor–ß Antagonizes Alveolar Type II Cell Proliferation Induced by Keratinocyte Growth FactorDepartments 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 This article has been cited by other articles:
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