Interferons and progesterone for establishment and maintenance of pregnancy: interactions among novel cell signaling pathways.
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Type I and/or type II interferons (IFNs) are important in establishing uterine receptivity to implantation in mammals. Gene expression effected by IFNs may be induced, stimulated or inhibited, but most are IFN-stimulated genes (ISGs). Effects of IFNs range from pregnancy recognition signaling in ruminants by IFN tau (IFNT) to effects on cellular functions of the uterus and uterine vasculature. For most, if not all, actions of IFNs on the uterus, progesterone (P(4)) is permissive to ISG expression, with genes being induced by IFN or induced by P(4) and stimulated by IFN. Uterine receptivity to implantation is P(4)-dependent; however, implantation events are preceded by loss of expression of progesterone (PGR) and estrogen (ESR1) receptors by uterine epithelia. Thus, P4 likely stimulates PGR-positive stromal cells to express one or more progestamedins, e.g., fibroblast growth factors-7 and -10, and/or hepatocyte growth factor, that act via their respective receptors on uterine epithelia and trophectoderm to regulate expression of ISGs. FGF10 appears to be the most important progestamedin in sheep uteri during pregnancy. Sequential effects of P(4) to induce and IFNs to stimulate gene expression suggest that P(4) and IFNs activate complimentary cell signaling pathways to modulate expression of genes for attachment of trophectoderm to uterine lumenal and superficial glandular epithelia (LE/sGE), modify phenotype of uterine stromal cells, silence PGR and ESR1 genes, signal pregnancy recognition, suppress genes for immune recognition, alter membrane permeability to enhance conceptus-maternal exchange of factors, increase endometrial vascularity and activate genes for transport of nutrients into the uterine lumen. In ewes, IFNT abrogrates the uterine luteolytic mechanism and stimulates expression of classical ISGs by GE and stromal cells, whereas LE/sGE express P(4)-induced and IFNT-stimulated genes important for uterine receptivity to implantation and conceptus development. These include wingless-type MMTV (mouse mammary tumor virus) integration site family member 7A (WNT7A) induced by IFNT, as well as galectin, proteases, protease inhibitors, transporters for glucose and amino acids, gastrin releasing polypeptide, insulin-like growth factor binding protein 1 and a hypoxia inducible factor. The specific functions of IFNs and ISGs induced in primates, pigs and other mammals during pregnancy are not known, but likely are important in establishment of pregnancy. Understanding the roles of IFNs and ISGs in uterine receptivity for implantation is necessary to develop strategies to enhance reproductive health and fertility in humans and domestic animals. The magnitude of the LH surge was reduced in cows receiving endotoxin.