Opposite Regulation of Transforming Growth Factors-β2 and -β3 Expression in the Human Endometrium

Abstract

TGF-betas have been reported to mediate the repression by progesterone of several matrix metalloproteinases in the human endometrium, thereby preventing menstrual breakdown. Because of conflicting reports on the expression profiles, source, and regulation of the TGF-beta system in this tissue, we investigated by real-time RT-PCR and ELISA the expression of the three TGF-betas (total and mature forms) and their two receptors throughout the menstrual cycle, and their regulation by ovarian steroids in cultured explants including their microdissected epithelial and stromal compartments. Regulation by cAMP and MAPK was further investigated. This comprehensive study on a large collection of endometrial samples evidenced a differential regulation of TGF-beta isoforms expression, both in vivo and in explant culture. In vivo, TGF-beta2 increased by about 5-fold at the mid-late secretory phase then declined after menstruation; TGF-beta3 increased at menstruation and remained high during the proliferative phase; TGF-beta1 was maximal at menstruation. In explants cultured without ovarian steroids both TGF-beta2 and -beta3 were preferentially expressed in the stroma. Ovarian steroids strongly repressed both TGF-beta2 and -beta3 in stroma but only TGF-beta2 in glands. cAMP prevented inhibition by ovarian steroids of TGF-beta2 but not -beta3. In presence of ovarian steroids, MAPK inhibitors (p38 and ERK pathways) stimulated TGF-beta3 but inhibited TGF-beta2 expression. In conclusion, TGF-beta2 and -beta3 are differentially expressed during the menstrual cycle and regulated by progesterone in epithelial vs stromal cells. The opposite regulation of TGF-beta2 and -beta3 by cAMP and MAPK could account for their distinct expression in vivo.