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Prostaglandin (PG) F₂ Receptor Expression and Signaling in Human Endometrium: Role of PGF₂ in Epithelial Cell Proliferation

Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, Edinburgh EH16 4SB, United Kingdom

Address all correspondence and requests for reprints to: Dr. Henry N. Jabbour, Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, United Kingdom. E-mail: h.jabbour{at}hrsu.mrc.ac.uk.

Prostaglandin (PG) F₂, 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. PGF₂ 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 PGF₂ 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 PGF₂ in endometrial epithelial cells. Ishikawa cells endogenously express the FP receptor, and treatment with 1–100 nM PGF₂ elicits a concentration-dependent increase in inositol phosphate release. Moreover, treatment of Ishikawa cells with 100 nM PGF₂ 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 PGF₂ 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 PGF₂-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 PGF₂ in epithelial cell proliferation via a PLC-dependent pathway.

Abbreviations: COX, Cyclooxygenase; DMSO, dimethylsulfoxide; FITC, fluorescein isothiocyanate; FP, PGF₂ receptor; GPCR, G-protein-coupled receptor; ISH, in situ hybridization; MEK, MAPK kinase; PG, prostaglandin; PLC, phospholipase C; RT, reverse transcription.

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