Molecular and cellular analysis of autocrine and paracrine functions of endometrial growth factors

子宫内膜细胞的生长和功能受雌激素和孕激素的调节。这些性类固醇激素的作用被认为是由子宫内膜内产生的生长因子和细胞因子介导的。本研究旨在阐明小鼠子宫内膜生长因子和细胞因子基因表达的分子和细胞调控机制。雌二醇刺激胰岛素样生长因子-I、表皮生长因子、转化生长因子-α、转化生长因子-α和转化生长因子-β2基因转录，并降低白介素18mRNA水平。孕酮可降低转化生长因子-β-1和转化生长因子-β-3m RNA水平。因此，所研究的所有生长因子的基因表达都受雌激素或孕激素的调节。我们的体外研究表明，胰岛素样生长因子-I、表皮生长因子和转化生长因子-α可促进子宫内膜细胞的复制。IGF-I在DNA复制中的作用是由IGF-I型受体通过MAPK和PI3K途径介导的。ESTR…的组合更多的二醇孕酮刺激子宫内膜间质细胞的DNA复制，性类固醇的这种刺激作用被EGF受体抑制剂RG13022减弱。这一结果表明，雌激素和孕酮的联合刺激作用是通过EGF家族生长因子配体的EGF受体信号转导实现的。这些生长因子在雌激素刺激下调节子宫内膜细胞的增殖。雌激素和转化生长因子-α降低雌激素受体α的表达水平，提示雌激素作用于雌激素受体水平的负反馈系统。基质金属蛋白酶(MMPs)被认为与子宫内膜的生长和重塑有关。检测MMP3、MMP7和MMP9在小鼠子宫内膜中的表达。在成年小鼠发情期，这些MMPm RNA水平升高。在体外研究中，雌二醇会在24小时内降低MMP3的mRNA水平。提示生长因子、细胞因子和基质金属蛋白酶与子宫内膜的生长和功能密切相关。较少

The growth and functions of uterine endometrial cells are regulated by estrogen and progestins. The actions of these sex steroid hormones are thought to be mediated by growth factors and cytokines produced, within the endometrium. The present study was aimed to clarify molecular and cellular regulatory mechanism of gene expression of growth factors and cytokines in the mouse endometrium. Estradiol stimulated transcription of insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), transforming growth factor a (TGF-α), and TGF-β2 genes, and decreased interleukin-18 (IL-18) mRNA level. Progesterone decreased TGF-β1 and TGF-β3 mRNA levels. Thus, the gene expression of all growth factors studied is regulated by estrogen or progestin. Our in vitro study revealed that IGF-I, EGF and TGF-α stimulated DNA replication of endometrial cells. The IGF-I action in terms of DNA replication was mediated by IGF-I type I receptors through MAPkinase and PI3kinase pathways. Combination of estr … More adiol and progesterone stimulated the DNA replication of endometrial stroma cells, and this stimulatory action of the sex steroids was reduced by an EGF-receptor inhibitor RG13022. This result indicates that the stimulatory action by combination of estradiol and progesterone is mediated through EGF receptor signaling using ligands of EGF family-growth factors. These growth factors regulate proliferation of endometroial cells under stimulatory stimuli of estrogen. Estradiol and TGF-α decreased estrogen receptorα mRNA level, suggesting negative feedback system of estrogen action at the estrogen receptor level. Matrix metaloproteinases (MMPs) are thought to be associated with the growth and remodeling of the endometrium. MMP3, MMP7 and MMP9 mRNA levels were analyzed in mouse endometrium. These MMP mRNA levels increased at estrus, in adult mice. In vitro study estradiol decreased MMP3 mRNA levels at 24 hours. The findings altogether suggest that growth factors, cytokines and MMPs are associated with the growth and functions of uterine endometrium. Less