Regulation of plasminogen activator inhibitor (PAI)-1 expression in a human trophoblast cell line by glucocorticoid (GC) and transforming growth factor (TGF)-beta.
Plasminogen activator inhibitor (PAI)-1 plays a key role in the regulation of fibrinolysis and cellular invasion by virtue of suppression of plasminogen activator function. Excessive production of placental PAI-1 has been associated with aberrant periplacental fibrin deposition in pregnancies complicated by pre-eclampsia (PE) and intrauterine growth restriction (IUGR). In the current study we used HTR-8/SVneo cells and primary cultures of cytotrophoblasts as models for study of PAI-1 regulation by transforming growth factor (TGF)-beta, and dexamethasone (DEX), a synthetic glucocorticoid (GC). ELISA and Northern blotting assays revealed that DEX treatment significantly enhanced TGF-beta effects on PAI-1 protein and mRNA expression in HTR-8/SVneo cells and cytotrophoblasts. These effects were GC-specific in that DEX and cortisol, but not estradiol, progesterone or testosterone, augmented PAI-1 levels in TGF-beta-treated cells. Conversely, DEX and TGF-beta treatment suppressed PAI-2 levels in HTR-8/SVneo cells and did not affect PAI-2 levels in cytotrophoblasts. PAI-1 promoter assays revealed that TGF-beta, but not DEX, enhanced PAI-1 expression in HTR-8/SVneo cells through a transcriptional mechanism. These results suggest that GC and TGF-beta may alter fibrinolytic and invasive properties of trophoblasts through their effects on PAI-1 expression.
Ma
Y
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Department of Obstetrics and Gynecology, New York University School of Medicine, 550 First Ave, New York, NY 10016, USA.
Ryu
J S
JS
Dulay
A
A
Segal
M
M
Guller
S
S
D015152:Blotting, Northern; D003907:Dexamethasone / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014327:Trophoblasts / Q000378:metabolism*
D005938:Glucocorticoids; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003907:Dexamethasone; D006854:Hydrocortisone