The activation of plasminogen activator inhibitor-1 expression by IL-1beta is attenuated by estrogen in hepatoblastoma HepG2 cells expressing estrogen receptor alpha.
A low estrogen status in postmenopausal women is associated with elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1). In this study, the ability of estrogen compounds to regulate PAI-1 expression was determined in a hepatocyte HepG2 cell line made to stably express estrogen receptor alpha (ERalpha). In both the wild type and ER expressing HepG2 cells, estrogen had no effect on basal PAI-1 expression. However, in the ER expressing cells the ability of IL-1beta to increase PAI-1 mRNA and protein levels was attenuated by 17beta-estradiol, tamoxifen and twelve estrogen components of Premarin. In contrast, the mixed agonist/antagonist raloxifene had weak agonist activity and like the pure antagonist ICI 182780, it dose dependently blocked the effect of 17beta-estradiol on IL-1beta stimulated PAI-1 levels. These results suggest that estrogen agonists may lower PAI-1 levels in vivo by inhibiting cytokine activated PAI-1 expression by an ER dependent mechanism.
Kilbourne
E J
EJ
Women's Health Research Institute, Wyeth-Ayerst Research, Radnor, PA 19087, USA. Kilboue@war.wyeth.com
Scicchitano
M S
MS
D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018197:Hepatoblastoma / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D011960:Receptors, Estrogen / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; D004967:Estrogens; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D011960:Receptors, Estrogen