Trophoblast derived prostaglandin E2 receptor 2 (EP2) is downregulated in recurrent miscarriage and regulates cell proliferation and inflammatory cytokines in vitro

Objectives Prostaglandin E2 acts as inflammatory mediator, modulates cytokines and regulates immune responses in reproductive processes via its various membrane receptors. Previously, we demonstrated that EP3 signalling plays a pivotal role in regulating the inflammatory microenvironment, hormone production and extracellular matrix remodelling at the feto-maternal interface of patients suffering from recurrent miscarriages (RM). Here we further analyze the role of EP2 in RM.

Materials and methods Expression patterns of EP2 in placental tissues of RM patients were analyzed with immunohistochemical and double immunofluorescence staining using paraffin-embedded sections of 38 human placentae (RM vs. healthy controls, n=19).

In vitro, viability and proliferation of HTR-8/SVneo cells were investigated in response to the selective EP2-antagonist PF-04418948. Additionally, culture supernatants were collected and the concentrations of hormones and inflammatory cytokines were analyzed by Enzyme-linked Immunosorbent Assay.

Results The expression of EP2 was decreased in syncytium and decidual cells of RM patients compared to controls. In our cell-culture-approach, we were able to demonstrate that the selective EP2-antagonist PF-04418948 reduced proliferation and secretion of βhCG in HTR-8/SVneo cells. Interestingly, PF-04418948 inhibited the production of the inflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8) and upregulated the expression of tumor necrosis factor-α (TNF-α) and plasminogen activator inhibitor type 1 (PAI-1) in HTR-8/SVneo cells.

Conclusions EP2 plays a vital role in regulating the balance of the inflammatory microenvironment and hormone secretion during implantation and early pregnancy. Alterations in the level of EP2 expression may contribute to RM thus offering a potential target for further research and therapeutic interventions.

Publication History

Article published online:
07 October 2020