Transforming growth factor-beta antagonizes alveolar type II cell proliferation induced by keratinocyte growth factor.
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)-beta 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-beta 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-beta. 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 p15(Ink4b) and p27(Kip1) protein levels were decreased. TGF-beta markedly inhibited alveolar epithelial cell proliferation induced by KGF. TGF-beta inhibited cdk2 enzyme activity and Rb phosphorylation and increased p15(Ink4b) protein levels. TGF-beta also inhibited differentiation induced by KGF as measured by secretion of surfactant protein-A into the apical media. In summary, TGF-beta inhibits the proliferative effect of KGF in vitro and may be a biologic antagonist of KGF.
Zhang
Feijie
F
National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
Nielsen
Larry D
LD
Lucas
Joseph J
JJ
Mason
Robert J
RJ
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050762:Cyclin-Dependent Kinase Inhibitor p15; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016160:Retinoblastoma Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000378:metabolism
C493966:CDKN2B protein, human; C493969:Cdkn2b protein, rat; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; C496453:FGF7 protein, human; C496455:Fgf7 protein, rat; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D018844:Cyclin-Dependent Kinases; C517004:CDC25A protein, human; C517007:Cdc25a protein, rat; D020687:cdc25 Phosphatases