Study on the hormonal regulation of human endometrial Immune system and its pathophysiological significance.

在人子宫内膜中，细胞因子和免疫细胞对着床所需的子宫内膜细胞增殖和分化起着非常重要的作用。此外，这些都是维持妊娠不可缺少的因素。研究表明，子宫内膜自然杀伤细胞（NK）和子宫内膜树突状细胞（DOs）在子宫内膜免疫系统的调控中起关键作用。利用人cDNA表达阵列技术，发现人IL-15基因在子宫内膜分泌期较增殖期表达上调。在人子宫内膜间质细胞体外脱胞系统中，IL-15 mRNA的表达不受雌激素的影响，而受孕激素的影响。但在培养过程中，IL-15的产生通过添加雌激素而增强。由于子宫内膜NK细胞具有IL-15受体并在体外受IL-15增殖，因此IL-15被认为是人子宫内膜中孕激素作用的中介。在妊娠后期，髓样dc增加，而淋巴样dc逐渐减少。在培养物中添加hCG显著诱导了两个DC亚群的成熟，并且在两个亚群中都发现了hCG受体，这表明子宫内膜免疫系统受到hCG和黄体酮的调节。进一步的微阵列分析显示黄体酮诱导的IL-1受体1型、纤维蛋白1、纤维蛋白2、微粒体谷胱甘肽s -转移酶1、富马酰乙酸水解酶和孤儿G蛋白偶联受体基因。我们在体外和体内证实了纤维蛋白的基因表达，发现纤维蛋白是黄体酮在人子宫内膜蜕膜过程中不可缺少的中介。

In human endometrium, cytokines and immune cells play very important role(s) for endometrial cell proliferation and differentiation required for implantation. In addition, these are indispensable factors for the maintenance of pregnancy. And It has been suggested that endometrial natural killer(NK) cells and endometrial dendritic cells(DOs) play key roles in the regulation of endometrial immune system. By using human cDNA expression array, human IL-15 gene was identified as an up-regulated transcriptional product during the secretory phase endometrium in comparison with the proliferative one. In vitro decidualization system with human endometrial stromal cells, it was demonstrated that the expression of IL-15 mRNA is up-regulated by progesterone not by estrogen. But the production of IL-15 during the culture was enhanced by the addition of estrogen. Since endometrial NK cells have receptors for IL-15 and proliferated by rIL-15 in vitro, IL-15 is believed to be a mediator of progesterone action in human endometrium. During pregnancy, myeloid DCs increased in the late stage, while lymphoid DCs decreased gradually. The addition of hCG to cultures significantly induced the maturation of both DC subsets, and hCG receptor was found in both subsets, indicating that endometrial immune systems are modulated by hCG as well as progesterone. Further analysis with microarray system revealed the progesterone-induced genes of IL-1 receptor type 1, fiburin-1,fiburin-2,microsomal glutathione S-transferase 1,fumarylacetoacetate hydrolase and orphan G protein-coupled receptor. We confirmed the in vitro as well in vivo gene expression of fiburins and found that the fiburins are indispensable mediator for progesterone action in human endometrial decidualization.