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Immunol."],"abstract":"<jats:p>Estradiol (E<jats:sub>2<\/jats:sub>) and progesterone (P) have potent effects on immune function in the human uterine endometrium which is essential for creating an environment conducive for successful reproduction. Type III\/lambda (\u03bb) interferons (IFN) are implicated in immune defense of the placenta against viral pathogens, which occurs against the backdrop of high E<jats:sub>2<\/jats:sub> and P levels. However, the effect of E<jats:sub>2<\/jats:sub> and P in modulating the expression and function of IFN\u03bb1 in the non-pregnant human uterine endometrium is unknown. We generated purified <jats:italic>in vitro<\/jats:italic> cultures of human uterine epithelial cells and stromal fibroblast cells recovered from hysterectomy specimens. Poly (I:C), a viral dsRNA mimic, potently increased secretion of IFN\u03bb1 by both epithelial cells and fibroblasts. The secretion of IFN\u03bb1 by epithelial cells significantly increased with increasing age following poly (I:C) stimulation. Stimulation of either cell type with E<jats:sub>2<\/jats:sub> (5x10<jats:sup>-8<\/jats:sup>M) or P (1x10<jats:sup>-7<\/jats:sup>M) had no effect on expression or secretion of IFN\u03bb1 either alone or in the presence of poly (I:C). E<jats:sub>2<\/jats:sub> suppressed the IFN\u03bb1-induced upregulation of the antiviral IFN-stimulated genes (ISGs) MxA, OAS2 and ISG15 in epithelial cells, but not fibroblasts. Estrogen receptor alpha (ER\u03b1) blockade using Raloxifene indicated that E<jats:sub>2<\/jats:sub> mediated its inhibitory effects on ISG expression <jats:italic>via<\/jats:italic> ER\u03b1. In contrast to E<jats:sub>2<\/jats:sub>, P potentiated the upregulation of ISG15 in response to IFN\u03bb1 but had no effect on MxA and OAS2 in epithelial cells. Our results demonstrate that the effects of E<jats:sub>2<\/jats:sub> and P on IFN\u03bb1-induced ISGs are cell-type specific. E<jats:sub>2<\/jats:sub>-mediated suppression, and selective P-mediated stimulation, of IFN\u03bb1-induced ISG expression in uterine epithelial cells suggest that the effects of IFN\u03bb1 varies with menstrual cycle stage, pregnancy, and menopausal status. The suppressive effect of E<jats:sub>2<\/jats:sub> could be a potential mechanism by which ascending pathogens from the lower reproductive tract can infect the pregnant and non-pregnant endometrium.<\/jats:p>","DOI":"10.3389\/fimmu.2021.718380","type":"journal-article","created":{"date-parts":[[2021,9,24]],"date-time":"2021-09-24T20:30:28Z","timestamp":1632515428000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Sex Hormones and Aging Modulate Interferon Lambda 1 Production and Signaling by Human Uterine Epithelial Cells and Fibroblasts"],"prefix":"10.3389","volume":"12","author":[{"given":"Mickey V.","family":"Patel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"Hopkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona 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