Seval Yasemin, Cakmak Hakan, Kayisli Umit A, Arici Aydin
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.
J Clin Endocrinol Metab. 2006 Jun;91(6):2349-57. doi: 10.1210/jc.2005-2132. Epub 2006 Mar 7.
Estrogen predominantly exerts its biological effects through the genomic pathway by binding to its intracellular receptors, interacting with the estrogen response element located in the promoter region of the target gene, and thus regulating gene transcription. There has been an increasing body of evidence regarding nongenomic actions of estrogen. Estrogen activates multiple signaling cascades, including the MAPK pathway. p38 MAPK plays key roles in mediating apoptosis, proliferation, and inflammation, which all take place in the endometrium during cyclical changes under the influence of estrogen.
We hypothesized that estrogen might activate the p38 MAPK pathway in endometrial cells and exert some of its actions through this pathway in the endometrium.
p38 MAPK phosphorylation was analyzed using in vivo and in vitro techniques.
Total and phosphorylated p38 MAPK immunostainings were more intense in epithelial cells compared with stromal cells, and the phosphorylated/total p38 MAPK ratio was significantly higher in the functional endometrial layer compared with the basal layer (P < 0.05). Estradiol significantly increased p38 MAPK phosphorylation in endometrial stromal cells in culture within 2 min (P < 0.05), and this phosphorylation was blocked by a specific p38 MAPK inhibitor. Moreover, tamoxifen and raloxifene also increased phosphorylation of p38 MAPK. The estrogen receptor antagonist ICI 182,780 reversed the estrogen-induced p38 MAPK phosphorylation in endometrial stromal and epithelial cells, suggesting involvement of the estrogen receptor.
Our results indicate the involvement of estrogen in regulating p38 MAPK activity in endometrial cells, suggesting a nongenomic action of estrogen through this MAPK in the endometrium.
雌激素主要通过基因组途径发挥其生物学效应，即与细胞内受体结合，与位于靶基因启动子区域的雌激素反应元件相互作用，从而调节基因转录。关于雌激素的非基因组作用，已有越来越多的证据。雌激素激活多种信号级联反应，包括丝裂原活化蛋白激酶（MAPK）途径。p38 MAPK在介导细胞凋亡、增殖和炎症中起关键作用，这些过程都发生在雌激素影响下子宫内膜的周期性变化中。
我们假设雌激素可能激活子宫内膜细胞中的p38 MAPK途径，并通过该途径在子宫内膜发挥某些作用。
使用体内和体外技术分析p38 MAPK磷酸化。
与基质细胞相比，上皮细胞中总p38 MAPK和磷酸化p38 MAPK的免疫染色更强，与基底层相比，功能层子宫内膜中磷酸化/总p38 MAPK比值显著更高（P<0.05）。雌二醇在2分钟内显著增加培养的子宫内膜基质细胞中p38 MAPK的磷酸化（P<0.05），且这种磷酸化被特异性p38 MAPK抑制剂阻断。此外，他莫昔芬和雷洛昔芬也增加p38 MAPK的磷酸化。雌激素受体拮抗剂ICI 182,780可逆转雌激素诱导的子宫内膜基质和上皮细胞中p38 MAPK的磷酸化，提示雌激素受体参与其中。
我们的结果表明雌激素参与调节子宫内膜细胞中p38 MAPK的活性，提示雌激素通过该MAPK在子宫内膜发挥非基因组作用。
