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

在人类子宫内膜中，细胞因子和免疫细胞对着床所需的子宫内膜细胞的增殖和分化起着非常重要的作用(S)。此外，这些都是维持妊娠不可或缺的因素。研究表明，子宫内膜自然杀伤细胞(NK细胞)和子宫内膜树突状细胞(DoS)在子宫内膜免疫系统的调节中起关键作用。利用人基因表达谱芯片，发现人IL-15基因是分泌期子宫内膜较增生期上调的转录产物。在人子宫内膜间质细胞体外蜕膜系统中，IL-15mRNA的表达受孕酮的上调，而不受雌激素的影响。但在培养过程中，雌激素的加入促进了IL-15的产生。由于子宫内膜NK细胞具有IL-15受体，并在体外被rIL-15刺激增殖，IL-15被认为是人子宫内膜孕酮作用的中介物。妊娠晚期髓系树突状细胞逐渐增多，淋巴样树突状细胞逐渐减少。加入hCG可显著促进两种DC亚群的成熟，且两种亚群均存在hCG受体，提示子宫内膜免疫系统受hCG和孕激素的调节。进一步的基因芯片分析揭示了孕酮诱导的IL-1受体1、纤溶酶原1、纤溶酶2、微粒体谷胱甘肽S转移酶1、延胡索酸乙酰乙酸酯水解酶和孤儿G蛋白偶联受体等基因。我们证实了fiburins在体外和体内的基因表达，发现fiburins是人子宫内膜蜕膜化中孕酮作用不可或缺的介体。

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.