{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T10:26:50Z","timestamp":1771928810745,"version":"3.50.1"},"reference-count":44,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T00:00:00Z","timestamp":1677024000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Rep Immunol"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Problem<\/jats:title><jats:p>Endometriosis is a proliferative disease characterized by cytokine\u2010induced inflammation. The objective of this study was to assess cell growth and PGE<jats:sub>2<\/jats:sub> production induced by TNF\u2010\u03b1 in endometriotic stromal cells (ESCs) in spheroid cell culture and to identify the signaling pathway involved with a view to finding new therapeutic targets for endometriosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method of study<\/jats:title><jats:p>Tissue samples were collected from patients with and without endometriosis. ESCs were isolated from ovarian endometrioma (OE). Gene expression was evaluated by real\u2010time PCR and DNA microarray analysis, the proliferative effect on ESCs by WST\u20108 assay, and PGE<jats:sub>2<\/jats:sub> production by ELISA. Protein phosphorylation was detected using western blotting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>COX\u20102, aromatase and VEGFA mRNA expression and PGE<jats:sub>2<\/jats:sub> production were significantly elevated in spheroid cell cultures compared to monolayer cell cultures. TNF\u2010\u03b1 receptor (TNFR) 1 and TNFR2 mRNA was also significantly increased. TNF\u2010\u03b1 promoted the proliferation and PGE<jats:sub>2<\/jats:sub> production of ESCs in spheroid cell cultures significantly more than in monolayer cell cultures. TNF\u2010\u03b1 increased the expression of several genes related to the pathophysiology of endometriosis in spheroid ESCs. DNA microarray analysis revealed that the Tpl2 gene, which codes for a MAPK upstream of MEK, was upregulated in OE and endometrium with endometriosis compared to normal endometrium. TNF\u2010\u03b1 increased the phosphorylation and expression of Tpl2 and MEK, and Tpl2 and MEK inhibitors inhibited TNF\u2010\u03b1\u2010induced proliferation and PGE<jats:sub>2<\/jats:sub> production in spheroid ESCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The Tpl2\u2010MEK signaling pathway may play a critical role in the cell growth and PGE<jats:sub>2<\/jats:sub> production induced by TNF\u2010\u03b1 in spheroid ESCs.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aji.13689","type":"journal-article","created":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T09:25:51Z","timestamp":1676021151000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Tpl2\u2010MEK pathway plays a critical role in spheroid\u2010cultured endometriotic stromal cells"],"prefix":"10.1111","volume":"89","author":[{"given":"Toshiyuki","family":"Minami","sequence":"first","affiliation":[{"name":"Department of 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