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

Tomoko Makabe, Kaori Koga, Hiroshi Nagabukuro, Mari Asada, Erina Satake, Ayumi Taguchi, Arisa Takeuchi, Mariko Miyashita, Mariko Miyashita‐Ishiwata, Miyuki Harada, Tetsuya Hirata, Yasushi Hirota, Osamu Wada‐Hiraike, Osamu Wada-Hiraike, Tomoyuki Fujii, Yutaka Osuga
Molecular human reproduction · 2020 · vol. 27(1) · doi:10.1093/molehr/gaaa077 · PMID:33543288 · W3108501232
article OA: bronze CC0 ⤵ 7 in-corpus citations
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Selective EP2 and EP4 antagonists reduced DNA synthesis, cAMP accumulation, cytokine secretion, and aromatase expression in endometriotic stromal cells, and EP4 antagonists reduced cAMP and inflammatory gene expression in peritoneal macrophages.

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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.

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Condition tags

mesh:D004715endometriosisadenomyosis

MeSH descriptors

Azetidines Benzamides Endometriosis Endometrium Macrophages, Peritoneal Receptors, Prostaglandin Stromal Cells Adult Azetidines Benzamides Cells, Cultured Chemokines Chemokines Cyclic AMP Cyclic AMP DNA Replication DNA Replication Endometriosis Endometrium Endometrium

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (39)

Cited by (7)

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europepmc
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