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黄体酮的调控。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中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 （IGF-I）、表皮生长因子（EGF）、转化生长因子a （TGF-α）和TGF-β2基因转录，降低白细胞介素-18 (IL-18) mRNA水平。孕酮降低TGF-β1和TGF-β3 mRNA水平。因此，所研究的所有生长因子的基因表达都受到雌激素或黄体酮的调节。我们的体外研究表明，IGF-I、EGF和TGF-α刺激子宫内膜细胞DNA复制。IGF-I在DNA复制方面的作用是由IGF-I型受体通过MAPkinase和PI3kinase途径介导的。更多的二醇和孕酮可刺激子宫内膜基质细胞的DNA复制，而egf受体抑制剂RG13022可降低性类固醇的这种刺激作用。这一结果表明，雌二醇和孕酮的联合刺激作用是通过EGF受体信号传导介导的，使用EGF家族生长因子的配体。这些生长因子在雌激素的刺激下调节子宫内膜细胞的增殖。雌二醇和TGF-α降低雌激素受体α mRNA水平，提示雌激素受体水平存在雌激素作用的负反馈系统。基质金属蛋白酶（MMPs）被认为与子宫内膜的生长和重塑有关。分析小鼠子宫内膜中MMP3、MMP7、MMP9 mRNA表达水平。成年小鼠发情时这些MMP mRNA水平升高。体外研究雌二醇在24小时降低MMP3 mRNA水平。这些发现表明，生长因子、细胞因子和MMPs与子宫内膜的生长和功能有关。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