Use of selective PGE2 receptor antagonists on human endometriotic stromal cells and peritoneal macrophages.

Abstract

Non-hormonal therapeutic strategies for endometriosis are needed. The aim of this study was to characterize the effects of prostaglandin (PG)E2 receptor inhibitors to explore their potential as novel therapeutic strategies for endometriosis. The expression of PGE2 receptors (EP2 and EP4) in donated tissues from human ovarian endometriosis, adenomyosis and peritoneal endometriosis was examined using immunohistochemistry. Human endometriotic stromal cells (ESC) isolated from ovarian endometriotic tissue and peritoneal macrophages were treated with EP2 and EP4 antagonists. cAMP accumulation and the effect of EP antagonists were measured using cAMP assays. DNA synthesis in ESC was detected using bromodeoxyuridine incorporation analysis. Interleukin (IL)-6 and IL-8 protein levels in ESC supernatants were measured using ELISAs. mRNA expression level for aromatase by ESC, and selected cytokines by peritoneal macrophages was measured using RT-PCR. EP2 and EP4 receptors were expressed in cells derived from control and diseased tissue, ovarian endometriotic, adenomyotic and peritoneal lesions. A selective EP2 antagonist reduced DNA synthesis, cAMP accumulation and IL-1β-induced proinflammatory cytokine secretion and aromatase expression. A selective EP4 antagonist negated IL-1β-induced IL-6 secretion and aromatase expression. In peritoneal macrophages, EP expression was elevated in endometriosis samples but the EP4 antagonist reduced cAMP levels and expression of vascular endothelial growth factor, chemokine ligand 2 and chemokine ligand 3 mRNA. EP2 and EP4 are functioning in endometriosis lesions and peritoneal macrophages, and their selective antagonists can reduce EP-mediated actions, therefore, the EP antagonists are potential therapeutic agents for controlling endometriosis.

• Authors: Tomoko Makabe, Kaori Koga, Hiroshi Nagabukuro, Mari Asada, Erina Satake, Ayumi Taguchi, Arisa Takeuchi, Mariko Miyashita, Miyuki Harada, Tetsuya Hirata, Yasushi Hirota, Osamu Wada-Hiraike, Tomoyuki Fujii, Yutaka Osuga
• Journal: Molecular human reproduction (Mol Hum Reprod) Vol. 27 Issue 1 (01 22 2021) ISSN: 1460-2407 [Electronic] England
• PMID: 33543288 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: [email protected].

Chemical References

• (S)-4-(1-(5-chloro-2-(4-fluorophenyoxy) benzamido)ethyl) benzoic acid
• Azetidines
• Benzamides
• Chemokines
• Receptors, Prostaglandin
• Receptors, Prostaglandin E, EP2 Subtype
• Receptors, Prostaglandin E, EP4 Subtype
• Cyclic AMP
• 1-(4-fluorobenzoyl)-3-(((6-methoxy-2-naphthyl)oxy)methyl)azetidine-3-carboxylic acid

Topics

• Adult
• Azetidines (pharmacology)
• Benzamides (pharmacology)
• Cells, Cultured
• Chemokines (biosynthesis)
• Cyclic AMP (metabolism)
• DNA Replication (drug effects)
• Endometriosis (drug therapy)
• Endometrium (cytology, drug effects)
• Female
• Humans
• Macrophages, Peritoneal (drug effects)
• Protein Biosynthesis (drug effects)
• Real-Time Polymerase Chain Reaction
• Receptors, Prostaglandin (antagonists & inhibitors)
• Receptors, Prostaglandin E, EP2 Subtype (antagonists & inhibitors)
• Receptors, Prostaglandin E, EP4 Subtype (antagonists & inhibitors)
• Stromal Cells (drug effects)