GLUCOCORTICOID-INDUCED TROPOELASTIN EXPRESSION IS MEDIATED VIA TRANSFORMING GROWTH FACTOR-BETA(3)

Glucocorticoids play a central role in fetal lung maturation. As fibro blasts have been shown to be an important target cell for glucocortico ids 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 tropoelast in (TE). Using this cDNA as a TE probe, we confirmed that TE mRNA was expressed in a developmental, organ- and cell type-specific fashion. E xogenous glucocorticoids indeed increased the number of TE transcripts in fetal lung fibroblasts. Blockage of endogenous TGF-beta(3) product ion with antisense TGF-beta(3) oligonucleotides abrogated the stimulat ory effect of cortisol on TE mRNA production by fetal lung fibroblasts . Also, neutralizing antibodies to TGF-beta(3) blocked the cortisol-st imulated TE mRNA expression. Fetal lung fibroblasts expressed both TGF -beta type I and II receptors. Cortisol did not influence the expressi on of either receptor mRNA. Antisense TGF-beta type I receptor oligonu cleotides inhibited cortisol-induced TE mRNA expression. Cortisol acti vated the transcription of stable transfected cDNA for TGF-beta(3) und er the control of glucocorticoid-inducible long terminal repeat (LTR) promoter in RFL-6 fibroblasts. Induction of TGF-beta(3) in the transfe ctants was accompanied by a marked increase in TE mRNA. These findings suggest that glucocorticoids mediate their stimulatory effect on TE m RNA expression in fetal lung fibroblasts via an autocrine action of gl ucocorticoid-induced TGF-beta(3).