{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:24:02Z","timestamp":1790270642051,"version":"4.1.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T00:00:00Z","timestamp":1606953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Education, Culture, Sports"},{"name":"Science and Technology"},{"name":"Society for Women's Health Science Research and the Kanzawa Medical Research Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2013PCR. 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-1\u03b2-induced proinflammatory cytokine secretion and aromatase expression. A selective EP4 antagonist negated IL-1\u03b2-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.<\/jats:p>","DOI":"10.1093\/molehr\/gaaa077","type":"journal-article","created":{"date-parts":[[2020,11,21]],"date-time":"2020-11-21T12:12:33Z","timestamp":1605960753000},"source":"Crossref","is-referenced-by-count":15,"title":["Use of selective PGE2 receptor antagonists on human endometriotic stromal cells and peritoneal macrophages"],"prefix":"10.1093","volume":"27","author":[{"given":"Tomoko","family":"Makabe","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5057-4120","authenticated-orcid":false,"given":"Kaori","family":"Koga","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Nagabukuro","sequence":"additional","affiliation":[{"name":"Extra Value Generation Drug Discovery Unit, Takeda Pharmaceutical Company, Fujisawa, Kanagawa 251-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Asada","sequence":"additional","affiliation":[{"name":"Extra Value Generation Drug Discovery Unit, Takeda Pharmaceutical Company, Fujisawa, Kanagawa 251-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erina","family":"Satake","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayumi","family":"Taguchi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arisa","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko","family":"Miyashita","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1071-5600","authenticated-orcid":false,"given":"Miyuki","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9975-6208","authenticated-orcid":false,"given":"Tetsuya","family":"Hirata","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0241-9780","authenticated-orcid":false,"given":"Yasushi","family":"Hirota","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Wada-Hiraike","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Osuga","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,19]]},"reference":[{"key":"2021020416160816000_gaaa077-B1","doi-asserted-by":"crossref","first-page":"eaah6037","DOI":"10.1126\/scisignal.aah6037","article-title":"Proshaglandin E2-EP2 NF\u03baB signaling in macrophages as a potential therapeutic target for intracranial aneurysms","volume":"10","author":"Aoki","year":"2017","journal-title":"Sci Signal"},{"key":"2021020416160816000_gaaa077-B2","doi-asserted-by":"crossref","first-page":"9716","DOI":"10.1073\/pnas.1507931112","article-title":"Molecular and preclinical basis to inhibit PGE2 receptors EP2 and EP4 as a novel nonsteroidal therapy for endometriosis","volume":"112","author":"Arosh","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2021020416160816000_gaaa077-B3","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1210\/me.2009-0017","article-title":"Selective inhibition of prostaglandin E2 receptors EP2 and EP4 induces apoptosis of human endometriotic cells through suppression of ERK1\/2, AKT, NFkappaB, and beta-catenin pathways and activation of intrinsic apoptotic mechanisms","volume":"23","author":"Banu","year":"2009","journal-title":"Mol Endocrinol"},{"key":"2021020416160816000_gaaa077-B4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1146\/annurev.med.57.121304.131253","article-title":"NSAIDs and cancer prevention: targets downstream of COX-2","volume":"58","author":"Cha","year":"2007","journal-title":"Annu Rev Med"},{"key":"2021020416160816000_gaaa077-B5","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1177\/1933719118808923","article-title":"Alteration of myeloid-derived suppressor cells, chronic inflammatory cytokines, and exosomal miRNA contribute to the peritoneal immune disorder of patients with endometriosis","volume":"26","author":"Chen","year":"2019","journal-title":"Reprod Sci"},{"key":"2021020416160816000_gaaa077-B6","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.ejogrb.2004.02.007","article-title":"The treatment with a COX-2 specific inhibitor is effective in the management of pain related to endometriosis","volume":"116","author":"Cobellis","year":"2004","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"2021020416160816000_gaaa077-B7","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/0002-9378(84)90713-0","article-title":"Peritoneal fluid prostaglandins and prostanoids in women with endometriosis, chronic pelvic inflammatory disease, and pelvic pain","volume":"148","author":"Dawood","year":"1984","journal-title":"Am J Obstet Gynecol"},{"key":"2021020416160816000_gaaa077-B8","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.7150\/ijbs.15943","article-title":"Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway","volume":"12","author":"Gan","year":"2016","journal-title":"Int J Biol Sci"},{"key":"2021020416160816000_gaaa077-B9","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1111\/bph.13565","article-title":"The anti-inflammatory effects of PGE2 on human lung macrophages are mediated by the EP3 receptor","volume":"173","author":"Gill","year":"2016","journal-title":"Br J Pharmacol"},{"key":"2021020416160816000_gaaa077-B10","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1152\/ajprenal.00194.2017","article-title":"PGE2 regulates renin through E-prostanoid receptor 1 via PKC\/cAMP\/CREB pathway in M-1 cells","volume":"313","author":"Gonzalez","year":"2017","journal-title":"Am J Physiol Renal Physiol"},{"key":"2021020416160816000_gaaa077-B11","doi-asserted-by":"crossref","first-page":"44169.","DOI":"10.1038\/srep44169","article-title":"EP2 receptor antagonism reduces peripheral and central hyperalgesia in a preclinical mouse model of endometriosis","volume":"7","author":"Greaves","year":"2017","journal-title":"Sci Rep"},{"key":"2021020416160816000_gaaa077-B12","first-page":"1","article-title":"Serum and peritoneal fluid levels of interleukin-6 and interleukin-37 as biomarkers for endometriosis","volume":"11","author":"Jiang","year":"2019","journal-title":"Gynecol Endocrinol"},{"key":"2021020416160816000_gaaa077-B13","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4049\/jimmunol.1101029","article-title":"Regulation of immune responses by prostaglandin E2","volume":"188","author":"Kalinski","year":"2012","journal-title":"J Immunol"},{"key":"2021020416160816000_gaaa077-B14","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.fertnstert.2006.05.068","article-title":"Selective cyclo-oxygenase-2 inhibition induces regression of autologous endometrial grafts by down-regulation of vascular endothelial growth factor-mediated angiogenesis and stimulation of caspase-3-dependent apoptosis","volume":"87","author":"Laschke","year":"2007","journal-title":"Fertil Steril"},{"key":"2021020416160816000_gaaa077-B15","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.mce.2010.11.022","article-title":"Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits invasion of human immortalized endometriotic epithelial and stromal cells through suppression of metalloproteinases","volume":"332","author":"Lee","year":"2011","journal-title":"Mol Cell Endocrinol"},{"key":"2021020416160816000_gaaa077-B16","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0092-8674(00)80402-X","article-title":"Multiple female reproductive failures in cyclooxygenase 2-deficient mice","volume":"91","author":"Lim","year":"1997","journal-title":"Cell"},{"key":"2021020416160816000_gaaa077-B17","doi-asserted-by":"crossref","first-page":"2822","DOI":"10.1158\/0008-5472.CAN-15-0125","article-title":"Definition of prostaglandin E2-EP2 signals in the colon tumor microenvironment that amplify inflammation and tumor growth","volume":"75","author":"Ma","year":"2015","journal-title":"Cancer Res"},{"key":"2021020416160816000_gaaa077-B18","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1111\/cas.12475","article-title":"Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions","volume":"105","author":"Majumder","year":"2014","journal-title":"Cancer Sci"},{"key":"2021020416160816000_gaaa077-B19","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1093\/oxfordjournals.humrep.a019023","article-title":"Vascular endothelial growth factor (VEGF) concentrations are elevated in peritoneal fluid of women with endometriosis","volume":"11","author":"Mclaren","year":"1996","journal-title":"Hum Reprod"},{"key":"2021020416160816000_gaaa077-B20","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.fertnstert.2015.03.023","article-title":"Drospirenone induces decidualization in human eutopic endometrial stromal cells and reduces DNA synthesis of human endometriotic stromal cells","volume":"104","author":"Miyashita","year":"2015","journal-title":"Fertil Steril"},{"key":"2021020416160816000_gaaa077-B21","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.4049\/jimmunol.1300290","article-title":"Prostaglandin E2-EP3 signaling induces inflammatory swelling by mast cell activation","volume":"192","author":"Morimoto","year":"2014","journal-title":"J Immunol"},{"key":"2021020416160816000_gaaa077-B22","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1152\/physrev.1999.79.4.1193","article-title":"Prostanoid receptors: structures, properties and functions","volume":"79","author":"Narumiya","year":"1999","journal-title":"Physiol Rev"},{"key":"2021020416160816000_gaaa077-B23","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.fertnstert.2013.08.016","article-title":"Identification of multiple and distinct defects in prostaglandin biosynthetic pathways in eutopic and ectopic endometrium of women with endometriosis","volume":"100","author":"Rakhila","year":"2013","journal-title":"Fertil Steril"},{"key":"2021020416160816000_gaaa077-B24","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1016\/j.surg.2016.12.037","article-title":"Direct growth-inhibitory effects of prostaglandin E2 in pancreatic cancer cells in vitro through an EP4\/PKA-mediated mechanism","volume":"161","author":"Schmidt","year":"2017","journal-title":"Surgery"},{"key":"2021020416160816000_gaaa077-B25","first-page":"2841","article-title":"Bioinformatics approach reveals the key role of CXC motif chemokine receptor 2 in endometriosis development","volume":"18","author":"Tan","year":"2018","journal-title":"Mol Med Rep"},{"key":"2021020416160816000_gaaa077-B26","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1177\/1933719108324893","article-title":"Mechanistic and therapeutic implications of angiogenesis in endometriosis","volume":"16","author":"Taylor","year":"2009","journal-title":"Reprod Sci"},{"key":"2021020416160816000_gaaa077-B27","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1111\/aji.12282","article-title":"IL-1\u03b2 increases expression of tryptophan 2.3-dioxygenase and stimulates tryptophan catabolism in endometriosis stromal cells","volume":"72","author":"Urata","year":"2014","journal-title":"Am J Reprod Immunol"},{"key":"2021020416160816000_gaaa077-B28","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/S0002-9440(10)61195-9","article-title":"Suppression of matrix metalloproteinase-9 by prostaglandin E2 in peritoneal macrophage is associated with severity of endometriosis","volume":"167","author":"Wu","year":"2005","journal-title":"Am J Pathol"},{"key":"2021020416160816000_gaaa077-B29","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1093\/molehr\/8.12.1103","article-title":"Distinct mechanisms regulate cyclooxygenase-1 and -2 in peritoneal macrophages of women with and without endometriosis","volume":"8","author":"Wu","year":"2002","journal-title":"Mol Hum Reprod"},{"key":"2021020416160816000_gaaa077-B30","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1258\/ebm.2010.009321","article-title":"Prostaglandin E2: the master of endometriosis?","volume":"235","author":"Wu","year":"2010","journal-title":"Exp Biol Med (Maywood)"},{"key":"2021020416160816000_gaaa077-B31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S146239940700021X","article-title":"Endometriosis: disease pathophysiology and the role of prostaglandins","volume":"9","author":"Wu","year":"2007","journal-title":"Expert Rev Mol Med"},{"key":"2021020416160816000_gaaa077-B32","first-page":"13795","article-title":"Effect of tumor-associated macrophages on gastric cancer stem cell in omental milky spots and lymph node micrometastasis","volume":"8","author":"Zhang","year":"2015","journal-title":"Int J Clin Exp Pathol"},{"key":"2021020416160816000_gaaa077-B33","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1002\/eji.201747417","article-title":"MDSCs drive the process of endometriosis by enhancing angiogenesis and are a new potential therapeutic target","volume":"48","author":"Zhang","year":"2018","journal-title":"Eur J Immunol"},{"key":"2021020416160816000_gaaa077-B34","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41572-018-0008-5","article-title":". Endometriosis","volume":"4","author":"Zondervan","year":"2018","journal-title":"Nat Rev Dis Primers"}],"container-title":["Molecular Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/molehr\/advance-article-pdf\/doi\/10.1093\/molehr\/gaaa077\/34675731\/gaaa077.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/molehr\/article-pdf\/27\/1\/gaaa077\/36195567\/gaaa077.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/molehr\/article-pdf\/27\/1\/gaaa077\/36195567\/gaaa077.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T12:10:05Z","timestamp":1612786205000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/molehr\/article\/doi\/10.1093\/molehr\/gaaa077\/6017824"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,1]]},"references-count":34,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1,22]]}},"URL":"https:\/\/doi.org\/10.1093\/molehr\/gaaa077","relation":{},"ISSN":["1460-2407"],"issn-type":[{"value":"1460-2407","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,1,1]]},"published":{"date-parts":[[2021,1,1]]},"article-number":"gaaa077"}}