DIFFERENTIAL REGULATION OF THE PLASMINOGEN-ACTIVATOR INHIBITOR-1 (PAI-1) GENE-EXPRESSION BY GROWTH-FACTORS AND PROGESTERONE IN HUMAN ENDOMETRIAL STROMAL CELLS

Plasminogen activator inhibitor-1 (PAI-1) has important regulatory fun ctions in haemostasis, extracellular matrix turn-over and cell adhesio n. We studied PAI-1 gene expression in primary cultures of endometrial stromal cells, and found that PAI-1 protein and mRNA were increased b oth by agents associated with differentiation, i.e. progesterone and t ransforming growth factor beta(1) (TGF beta(1)), and by those promotin g proliferation, i.e. epidermal growth factor (EGF), TGF alpha and bas ic fibroblast growth factor (bFGF). In order to further elucidate the mechanism of regulation, we transfected stromal cells with an expressi on construct containing 804 bp of the PAI-1 promoter fused to a chlora mphenicol acetyl transferase (CAT) reporter gene. After stimulation wi th the polypeptide growth factors TGF beta 1, EGF and bFGF we found in creased CAT activity, indicating that these stimulators hard initiated interaction with the transfected promoter fragment. On the other hand , stimulation with progesterone did not increase CAT activity, even th ough these cells were perfectly able to respond with increased secreti on of PAI-1 protein. Run off experiments demonstrated that progesteron e increased the stability of PAI-I mRNA in endometrial stromal cells. We conclude that the polypeptide growth factors TGF beta 1, EGF and bF GF increase PAl-1 expression by increasing gene transcription. Progest erone, on the other hand, does not interact with the 804 bp promoter r egion, but increases the stability of PAI-1 mRNA.