Gonadotropin-releasing Hormone and TGF-beta Activate MAP Kinase and Differentially Regulate Fibronectin Expression in Endometrial Epithelial and Stromal Cells

Gonadotropin-releasing hormone analog (GnRHa) is used for medical management of endometriosis and premature luteinizing hormone surge during controlled ovarian stimulation. Human endometrium expresses GnRH receptors, and GnRHa alters the expression of transforming growth factor-beta (TGF-beta) and receptors in endometrial cells. Because the diverse biological actions of GnRHa and TGF-beta are mediated in part through the MAPK pathway, we determined whether utilization of MAPK/ERK and transcriptional activation of immediate early genes c-fos and c-jun result in differential regulation of fibronectin, known as key regulator of embryo implantation and endometriosis progression. Using endometrial stromal cells (ESC) and the endometrial epithelial cell line HES, we demonstrated that GnRHa and TGF-beta, in a dose-, time-, and cell-dependent manner, increased the level of phosphorylated ERK1/2 (pERK1/2). GnRH antagonist Antide also increased pERK1/2 induction in ESC and HES, whereas pretreatment reduced GnRHa-induced pERK2 in ESC but not in HES. Cotreatments with GnRHa plus TGF-beta1 did not have an additive or an inhibitory effect on pERK1/2 induction compared with GnRHa or TGF-beta1 action alone. TGF-beta1 and GnRHa increased ERK1/2 nuclear accumulation and inversely regulated the expression of c-fos and c-jun and that of fibronectin in a cell-specific manner. Pretreatment with U-0126, a MEK1/2 inhibitor, blocked basal, as well as GnRHa- and TGF-beta1-induced pERK1/2; however, it differentially affected c-fos, c-jun, and fibronectin expression. In conclusion, the results indicate that GnRHa and TGF-beta signaling through MAPK/ERK results in differential regulation of fibronectin expression in endometrial cells, a molecular mechanism where short- and long-term GnRHa therapy and locally expressed TGF-beta could influence embryo implantation and endometriosis implants, respectively.