Prostaglandin (PG) F2α Receptor Expression and Signaling in Human Endometrium: Role of PGF2α in Epithelial Cell Proliferation

Prostaglandin (PG) F2α, a member of the prostanoid bioactive lipid family, is secreted by human endometrium throughout the menstrual cycle and is present in both menstrual fluid and medium of endometrial explants in culture. PGF2α mediates its effects through a seven-transmembrane G-protein-coupled receptor (FP). The aim of this study was to examine the temporal expression, signaling, and role of FP receptor in the human endometrium. Quantitative RT-PCR analysis demonstrated highest expression of FP receptor in the mid- to late-proliferative phase, compared with early-proliferative and secretory phase endometrium. In situ hybridization studies localized FP receptor mRNA expression to the epithelial cell compartment during the mid- to late-proliferative phase. Moreover, treatment of endometrial tissue with 1–100 nm PGF2α induced a concentration-dependent increase in inositol phosphate mobilization, indicating functional FP receptor expression. The Ishikawa human endometrial epithelial cell line was used to investigate further the signaling and role of PGF2α in endometrial epithelial cells. Ishikawa cells endogenously express the FP receptor, and treatment with 1–100 nm PGF2α elicits a concentration-dependent increase in inositol phosphate release. Moreover, treatment of Ishikawa cells with 100 nm PGF2α induced phosphorylation of ERK1/2 that was abolished when cells were cotreated with 50 μm PD98059 (MAPK kinase inhibitor) or 10 μm U73122 [phospholipase C (PLC) inhibitor]. Treatment of Ishikawa cells with PGF2α for 24 h induced a significant concentration-dependent increase in Ishikawa cell proliferation. Coincubation of the cells with 50 μm PD98059 or 2 μm U73122 demonstrated that PLC inhibition significantly reduced PGF2α-induced proliferation, whereas MAPK kinase inhibition had no effect. In summary, these studies demonstrate increased FP receptor expression in endometrial epithelial cells during the proliferative phase of the menstrual cycle and identify a role for PGF2α in epithelial cell proliferation via a PLC-dependent pathway.