Shao Ruijin, Egecioglu Emil, Weijdegård Birgitta, Kopchick John J, Fernandez-Rodriguez Julia, Andersson Niklas, Billig Håkan
Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Gothenburg University, SE-41390, Gothenburg, Sweden.
Am J Physiol Endocrinol Metab. 2007 Nov;293(5):E1430-42. doi: 10.1152/ajpendo.00384.2007. Epub 2007 Sep 11.
Estrogen receptors (ERs) are members of the nuclear receptor superfamily and are involved in regulation of fallopian tube functions (i.e., enhancement of protein secretion, formation of tubal fluid, and regulation of gamete transport). However, the ER subtype-mediated mechanisms underlying these processes have not been completely clarified. Recently, we identified ERbeta expression and localization in rat fallopian tubes, suggesting a potential biological function of ERbeta related to calcium-dependent ciliated beating. Here we provide for the first time insight into the less studied ERalpha isoforms, which mediate estrogen-dependent production and secretion of IGFs in vivo. First, Western blot studies revealed that three ERalpha isoforms were expressed in mouse fallopian tubes. Subsequent immunohistochemical analysis showed that ERalpha was detected in all cell types, whereas ERbeta was mainly localized in ciliated epithelial cells. Second, ERalpha isoform levels were dramatically downregulated in mouse fallopian tubes by treatment with E(2) or PPT, an ERalpha agonist, in a time-dependent manner. Third, the presence of ICI 182,780, an ER antagonist, blocked the E(2)- or PPT-induced downregulation of tubal ERalpha isoform expression in mice. However, alteration of ERalpha immunoreactivity following ICI 182,780 treatment was only detected in epithelial cells of the ampullary region. Fourth, changes in ERalpha isoform expression were found to be coupled to multiple E(2) effects on tubal growth, protein synthesis, and secretion in mouse fallopian tube tissues and fluid. In particular, E(2) exhibited positive regulation of IGF-I and IGF-II protein levels. Finally, using growth hormone receptor (GHR) gene-disrupted mice, we showed that regulation by E(2) of IGF production was independent of GH-induced GHR signaling in mouse fallopian tubes in vivo. These data, together with previous studies from our laboratory, suggest that the long-term effects of estrogen agonist promote IGF synthesis and secretion in mouse tubal epithelial cells and fallopian tube fluid via stimulation of ERalpha.
雌激素受体（ERs）是核受体超家族的成员，参与输卵管功能的调节（即增强蛋白质分泌、形成输卵管液以及调节配子运输）。然而，这些过程背后的ER亚型介导机制尚未完全阐明。最近，我们在大鼠输卵管中鉴定出ERβ的表达和定位，提示ERβ与钙依赖性纤毛摆动相关的潜在生物学功能。在此，我们首次深入研究了较少被研究的ERα亚型，其在体内介导雌激素依赖性的胰岛素样生长因子（IGFs）产生和分泌。首先，蛋白质印迹研究显示三种ERα亚型在小鼠输卵管中表达。随后的免疫组织化学分析表明，ERα在所有细胞类型中均有检测到，而ERβ主要定位于纤毛上皮细胞。其次，用E（2）或ERα激动剂PPT处理小鼠输卵管后，ERα亚型水平以时间依赖性方式显著下调。第三，ER拮抗剂ICI 182,780的存在可阻断E（2）或PPT诱导的小鼠输卵管ERα亚型表达下调。然而，ICI 182,780处理后ERα免疫反应性的改变仅在壶腹部区域的上皮细胞中检测到。第四，发现ERα亚型表达的变化与E（2）对小鼠输卵管组织和液体中输卵管生长、蛋白质合成和分泌的多种作用相关。特别是，E（2）对IGF-I和IGF-II蛋白水平表现出正调控作用。最后，使用生长激素受体（GHR）基因敲除小鼠，我们表明E（2）对IGF产生的调节在体内小鼠输卵管中独立于生长激素诱导的GHR信号传导。这些数据，连同我们实验室之前的研究，表明雌激素激动剂的长期作用通过刺激ERα促进小鼠输卵管上皮细胞和输卵管液中IGF的合成和分泌。
