{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T01:38:25Z","timestamp":1792201105072,"version":"4.4.0"},"reference-count":82,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["PJT-180394#"],"award-info":[{"award-number":["PJT-180394#"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Progesterone (P4) withdrawal is the key trigger for labour onset. Labour is a sterile inflammatory process involving monocyte infiltration, differentiation into M1 or M2 macrophages (Macs) and contributing to the inflammatory milieu in the uterus. Premature leukocyte influx may lead to preterm birth. Inflammatory stimuli induce intracellular progesterone (P4) withdrawal in myometrial cells (MYOs) through activation of P4 metabolizing enzyme 20alpha-hydroxysteroid dehydrogenase (20\u03b1-HSD). We hypothesized that (1) the pro-inflammatory M1-Macs induce 20\u03b1-HSD in MYO, which causes P4 withdrawal and MYO contractility, and (2) IL-1\u03b1 produced by M1-Macs mediates the effect of M1-Macs on intracellular P4 withdrawal in MYO. Human myometrial biopsies from term pregnant women in labour (TL) and not in labour (TNL) revealed higher IL-1\u03b1 in TL, with M1-Macs in TNL expressing more IL-1\u03b1 than MYO. In vitro study shows (1) higher expression of IL-1\u03b1 in M1-Macs compared to M2-Macs; (2) treatment of MYO with IL-1\u03b1 or M1-Macs increased 20\u03b1-HSD and contractility; and (3) blockade of IL-1\u03b1, AP-1 transcription factors, or co-treatment with non-metabolizable progestin R5020 inhibit these effects. Our findings highlight the role of tissue-resident M1-Macs in regulating intracellular P4 metabolism and suggest that M1-Macs-derived IL-1\u03b1 may facilitate P4-withdrawal and uterine contractility associated with labour onset.<\/jats:p>","DOI":"10.3390\/cells14211692","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:02:01Z","timestamp":1761670921000},"page":"1692","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["M1 Macrophages Are a Source of IL-1\u03b1: A Driver of Progesterone Metabolism and Myometrial Contraction"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8243-0191","authenticated-orcid":false,"given":"Lubna","family":"Nadeem","sequence":"first","affiliation":[{"name":"Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxwell","family":"Librach","sequence":"additional","affiliation":[{"name":"Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Boros-Rausch","sequence":"additional","affiliation":[{"name":"Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Matthews","sequence":"additional","affiliation":[{"name":"Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Aguiar-Cabeza","sequence":"additional","affiliation":[{"name":"Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6084-8156","authenticated-orcid":false,"given":"Oksana","family":"Shynlova","sequence":"additional","affiliation":[{"name":"Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada"},{"name":"Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada"},{"name":"Department of Obstetrics & Gynecology, University of Toronto, Toronto, ON M5G 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen James","family":"Lye","sequence":"additional","affiliation":[{"name":"Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada"},{"name":"Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada"},{"name":"Department of Obstetrics & Gynecology, University of Toronto, Toronto, ON M5G 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1213\/ANE.0000000000000705","article-title":"Outcomes for extremely premature infants","volume":"120","author":"Glass","year":"2015","journal-title":"Anesth. 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