Bazer Fuller W, Burghardt Robert C, Johnson Greg A, Spencer Thomas E, Wu Guoyao
Texas A&M University, College Station, TX 77843-2471, USA.
Reprod Biol. 2008 Nov;8(3):179-211. doi: 10.1016/s1642-431x(12)60012-6.
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.
I型和/或II型干扰素（IFN）在哺乳动物建立子宫对植入的接受性方面很重要。受IFN影响的基因表达可能被诱导、刺激或抑制，但大多数是IFN刺激基因（ISG）。IFN的作用范围从反刍动物中IFN tau（IFNT）介导的妊娠识别信号到对子宫及其血管细胞功能的影响。对于IFN对子宫的大多数（如果不是全部）作用而言，孕酮（P4）允许ISG表达，这些基因由IFN诱导或由P4诱导并被IFN刺激。子宫对植入的接受性依赖于P4；然而，植入事件之前子宫上皮细胞会失去孕酮（PGR）和雌激素（ESR1）受体的表达。因此，P4可能刺激PGR阳性的基质细胞表达一种或多种孕激素介质，例如成纤维细胞生长因子-7和-10，和/或肝细胞生长因子，它们通过各自的受体作用于子宫上皮和滋养外胚层，以调节ISG的表达。FGF10似乎是绵羊孕期子宫中最重要的孕激素介质。P4诱导和IFN刺激基因表达的顺序效应表明，P4和IFN激活互补的细胞信号通路，以调节滋养外胚层附着于子宫腔和浅表腺上皮（LE/sGE）的基因表达，改变子宫基质细胞的表型，使PGR和ESR1基因沉默，发出妊娠识别信号，抑制免疫识别相关基因，改变膜通透性以增强胚胎与母体之间的因子交换，增加子宫内膜血管生成，并激活将营养物质转运到子宫腔的基因。在母羊中，IFNT消除子宫溶黄体机制，并刺激腺上皮（GE）和基质细胞表达经典的ISG，而LE/sGE表达对子宫接受植入和胚胎发育很重要的P4诱导和IFNT刺激基因。这些基因包括IFNT诱导的无翅型MMTV（小鼠乳腺肿瘤病毒）整合位点家族成员7A（WNT7A），以及半乳糖凝集素、蛋白酶、蛋白酶抑制剂、葡萄糖和氨基酸转运蛋白、胃泌素释放肽、胰岛素样生长因子结合蛋白1和一种缺氧诱导因子。在灵长类动物、猪和其他哺乳动物孕期诱导产生的IFN和ISG的具体功能尚不清楚，但可能对妊娠的建立很重要。了解IFN和ISG在子宫植入接受性中的作用对于制定改善人类和家畜生殖健康及生育能力的策略是必要的。接受内毒素的奶牛促黄体生成素（LH）峰值降低。
