Glucocorticoid-induced tropoelastin expression is mediated via transforming growth factor-beta(3)

Glucocorticoids play a central role in fetal lung maturation. As fibroblasts have been shown to be an important target cell for glucocorticoids in fetal lung, we have recently cloned several cDNAs representing genes induced by cortisol in fetal rat lung fibroblasts. Approximately 30% of the cDNAs were identified as transforming growth factor (TGF)-beta(3). Here, we selected and sequenced another cDNA. Analysis of DNA sequence homology indicated that this cDNA encodes the rat tropoelastin (TE). Using this cDNA as a TE probe, we confirmed that TE mRNA was expressed in a developmental, organ- and cell type-specific fashion. Exogenous glucocorticoids indeed increased the number of TE transcripts in fetal lung fibroblasts. Blockage of endogenous TGF-beta(3) production with antisense TGF-beta(3) oligonucleotides abrogated the stimulatory effect of cortisol on TE mRNA production by fetal lung fibroblasts. Also, neutralizing antibodies to TGF-beta(3) blocked the cortisol-stimulated TE mRNA expression. Fetal lung fibroblasts expressed both TGF-beta type I and II receptors. Cortisol did not influence the expression of either receptor mRNA. Antisense TGF-beta type I receptor oligonucleotides inhibited cortisol-induced TE mRNA expression. Cortisol activated the transcription of stable transfected cDNA for TGF-beta(3) under the control of glucocorticoid-inducible long terminal repeat (LTR) promoter in RFL-6 fibroblasts. Induction of TGF-beta(3) in the transfectants was accompanied by a marked increase in TE mRNA. These findings suggest that glucocorticoids mediate their stimulatory effect on TE mRNA expression in fetal lung fibroblasts via an autocrine action of glucocorticoid-induced TGF-beta(3).