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Published ahead of print on August 27, 2004, doi:10.1165/rcmb.2004-0182OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 6, December 2004, 679-686

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Submitted on June 8, 2004
Revised on August 27, 2004

TGF-{beta} antagonizes alveolar type II cell proliferation induced by KGF

Feijie Zhang1, Larry D Nielsen1, Joseph J Lucas1, and Robert J Mason1*

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

* To whom correspondence should be addressed. 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. Since 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 cdk2 kinase activity and Rb phosphorylation. Cyclin D1, cdk2, and cdc25A protein levels were increased, and p15Ink4b and p27Kip1 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 p15Ink4b protein levels. TGF-{beta} also inhibited differentiation induced by KGF as measured by secretion of SP-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.




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