TGF-beta1 inhibits surfactant component expression and epithelial cell maturation in cultured human fetal lung

Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine shown to play a critical role in organ morphogenesis, development, growth regulation, cellular differentiation, gene expression, and tissue remodeling after injury. We examined the effect of exogenously administered TGF-beta1...

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Published in:	The American journal of physiology Vol. 275; no. 5; pp. L950 - L960
Main Authors:	Beers, M F, Solarin, K O, Guttentag, S H, Rosenbloom, J, Kormilli, A, Gonzales, L W, Ballard, P L
Format:	Journal Article
Language:	English
Published:	United States 01-11-1998
Subjects:	Apoproteins - biosynthesis Apoproteins - genetics Cells, Cultured Dexamethasone - pharmacology Dose-Response Relationship, Drug Epithelial Cells - cytology Epithelial Cells - drug effects Epithelial Cells - physiology Fetus Humans Lung - cytology Lung - drug effects Lung - physiology Lung - ultrastructure Proteolipids - biosynthesis Proteolipids - genetics Pulmonary Surfactant-Associated Proteins Pulmonary Surfactants - biosynthesis Pulmonary Surfactants - genetics Recombinant Proteins - pharmacology RNA, Messenger - analysis Transcription, Genetic - drug effects Transforming Growth Factor beta - pharmacology Transforming Growth Factor beta - physiology
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Summary:	Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine shown to play a critical role in organ morphogenesis, development, growth regulation, cellular differentiation, gene expression, and tissue remodeling after injury. We examined the effect of exogenously administered TGF-beta1 on the expression of surfactant proteins (SPs) and lipids, fatty acid synthetase, and ultrastructural morphology in human fetal lung cultured for 5 days with and without dexamethasone (10 nM). Expression of the type II cell-specific marker surfactant proprotein C (proSP-C), studied by [35S]Met incorporation and immunoprecipitation, increased sevenfold with dexamethasone treatment. TGF-beta1 (0.1-100 ng/ml) in the presence of dexamethasone inhibited 21-kDa proSP-C expression in a dose-dependent manner (maximal inhibition 31% of control level at 100 ng/ml). There was no change in [35S]Met incorporation into total protein in any of the treatment groups vs. the control group. In immunoblotting experiments, TGF-beta1 blocked culture-induced accumulation of SP-A and SP-B. Under the same conditions, TGF-beta1 reduced mRNA content for SP-A, SP-B, and SP-C to 20, 38, and 41%, respectively, of matched control groups but did not affect levels of beta-actin mRNA. SP transcription rates after 24 h of exposure to TGF-beta1 were reduced to a similar extent (20-50% of control level). In both control and dexamethasone-treated explants, TGF-beta1 (10 ng/ml) also decreased fatty acid synthetase mRNA, protein, and enzyme activity and the rate of [3H]choline incorporation into phosphatidylcholine. By electron microscopy, well-differentiated type II cells lining potential air spaces were present in explants cultured with dexamethasone, whereas exposure to TGF-beta1 with or without dexamethasone resulted in epithelial cells lacking lamellar bodies. We conclude that exogenous TGF-beta1 disrupts culture-induced maturation of fetal lung epithelial cells and inhibits expression of surfactant components through effects on gene transcription.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0002-9513
DOI:	10.1152/ajplung.1998.275.5.L950