Sex Hormones and Aging Modulate Interferon Lambda 1 Production and Signaling by Human Uterine Epithelial Cells and Fibroblasts

Estradiol (E-2) 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 (lambda) interferons (IFN) are implicated in immune defense of the placenta against viral pathogens, which occurs against the backdrop of high E-2 and P levels. However, the effect of E-2 and P in modulating the expression and function of IFN lambda 1 in the non-pregnant human uterine endometrium is unknown. We generated purified in vitro 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 lambda 1 by both epithelial cells and fibroblasts. The secretion of IFN lambda 1 by epithelial cells significantly increased with increasing age following poly (I:C) stimulation. Stimulation of either cell type with E-2 (5x10(-8)M) or P(1x10(-7)M) had no effect on expression or secretion of IFN lambda 1 either alone or in the presence of poly (I:C). E-2 suppressed the IFN lambda 1-induced upregulation of the antiviral IFN-stimulated genes (ISGs) MxA, OAS2 and ISG15 in epithelial cells, but not fibroblasts. Estrogen receptor alpha (ER alpha) blockade using Raloxifene indicated that E-2 mediated its inhibitory effects on ISG expression via ER alpha. In contrast to E-2, P potentiated the upregulation of ISG15 in response to IFN lambda 1 but had no effect on MxA and OAS2 in epithelial cells. Our results demonstrate that the effects of E-2 and P on IFN lambda 1-induced ISGs are cell-type specific. E-2-mediated suppression, and selective P-mediated stimulation, of IFN lambda 1-induced ISG expression in uterine epithelial cells suggest that the effects of IFN lambda 1 varies with menstrual cycle stage, pregnancy, and menopausal status. The suppressive effect of E-2 could be a potential mechanism by which ascending pathogens from the lower reproductive tract can infect the pregnant and non-pregnant endometrium.