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Interleukin (IL)-1\u03b2 and prostaglandin (PG)F2\u03b1 are two key mediators implicated in preparing the uterus for labor by regulating the expression of uterine activation proteins (UAPs) and proinflammatory cytokines and chemokines. To investigate this process, primary human myometrial smooth muscle cells (HMSMC) isolated from the lower segment of women undergoing elective cesarean sections at term (not in labor) were used to test the inflammatory cytokine and UAP outputs induced by PGF2\u03b1 and IL-1\u03b2 alone or in sequential combinations. PGF2\u03b1 and IL-1\u03b2 regulate mRNA abundance of the PGF2\u03b1 receptor FP, the IL-1 receptor system, interleukin 6, and other UAPs (OXTR, COX2), driving positive feedback interactions to further amplify their own proinflammatory effects. Sequential stimulation of HMSMC by PGF2\u03b1 and IL-1\u03b2 in either order results in amplified upregulation of IL-6 and COX-2 mRNA and protein, compared to their effects individually. These profound increases were unique to myometrium and not observed with stimulation of human fetal membrane explants. These results suggest that PGF2\u03b1 and IL-1\u03b2 act cooperatively upstream in the birth cascade to maximize amplification of IL-6 and COX-2, to build inflammatory load and thereby promote uterine transition. Targeting PGF2\u03b1 or IL-1\u03b2, their actions, or intermediates (e.g. IL-6) would be an effective therapeutic intervention for preterm birth prevention or delay.<\/jats:p>","DOI":"10.1093\/biolre\/ioz029","type":"journal-article","created":{"date-parts":[[2019,2,23]],"date-time":"2019-02-23T02:19:26Z","timestamp":1550888366000},"page":"1370-1385","source":"Crossref","is-referenced-by-count":36,"title":["Cooperative effects of sequential PGF2\u03b1 and IL-1\u03b2 on IL-6 and COX-2 expression in human myometrial cells"],"prefix":"10.1093","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4232-7242","authenticated-orcid":false,"given":"Kelycia B","family":"Leimert","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0539-8877","authenticated-orcid":false,"given":"Barbara S 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Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3635-6538","authenticated-orcid":false,"given":"Xin","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Pediatrics, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9967-0084","authenticated-orcid":false,"given":"Sarah A","family":"Robertson","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Adelaide, Adelaide, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7923-5221","authenticated-orcid":false,"given":"Sylvain","family":"Chemtob","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, 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