CYTOKINE REGULATION OF TROPHOBLAST FUNCTION

在人类和灵长类动物中，滋养层细胞分泌的绒毛膜促性腺激素(CG)是母体识别怀孕的胚胎信号。CG是一种异二聚体糖蛋白激素，由一个α亚基和一个不同的CGβ亚基组成。胎盘细胞滋养层细胞分化为合体滋养层细胞后，受精后几天出现CG的表达。缺少CG会导致新的月经周期开始。据报道，细胞因子在调节CG的分泌方面发挥作用，并被认为调节细胞滋养层细胞的分化。在这些细胞因子中，白介素6(IL-6)和白血病抑制因子(LIF；属于同一细胞因子家族的成员)已被证明在妊娠过程中起着重要作用。LIF在胚泡着床时由子宫产生，在体外可以刺激滋养外胚层的增殖。IL-6由子宫胎盘单位内外的多种细胞分泌，包括滋养层细胞本身，因此可以自分泌的方式诱导CG的分泌。滋养层细胞通过接触促炎细胞因子IL-1来刺激IL-6的产生。因此，子宫炎症导致CG分泌改变是可行的。此外，被诊断为妊娠障碍的妇女，即先兆子痫，血浆IL-6水平升高，这与循环中CG水平升高有关。这些和其他数据暗示IL-6参与滋养细胞生理学和病理生理学。以下具体目标旨在开始解决IL-6调节滋养层细胞分化和CG分泌的假设。具体目的I：确定IL-6在调节滋养层细胞增殖和分化中的作用。特定目的II：利用基因芯片技术研究IL-6对滋养层细胞基因表达的调节。JAR绒毛膜癌细胞和细胞滋养层细胞的原代培养将用于解决这些目标。预计从这些实验中获得的数据将确定IL-6是滋养层功能的关键调节因子，并将开始阐明IL-6如何调节滋养层细胞的分化。这些研究的长期目标是更好地了解母体/胎儿细胞因子对滋养层功能的调节，以及最终滋养层分泌产物如何调节母体免疫系统以维持妊娠。

In humans and primates, trophoblast secretion of chononic gonadotropin (CG) serves as the embryonic signal for maternal recognition of pregnancy. CG is a heterodimeric glycoprotein hormone composed of an alpha-subunit and a distinct CGbeta-subunit. Expression of CG occurs a few days subsequent to fertilization following differentiation of placental cytotrophoblasts into syncytiotrophoblasts. Absence of CG results in the initiation of a new menstrual cycle. Cytokines have been reported to play a role in regulating secretion of CG and have been postulated to modulate cytotrophoblast differentiation. Of these cytokines, interleukin- 6 (IL-6) and leukemia inhibitory factor (LIF; members of the same cytokine family) have been shown to have important roles during pregnancy. LIF is produced by the uterus at the time of blastocyst implantation and can stimulate trophectoderm proliferation in vitro. IL-6 is secreted from a number of cell types within and outside the uteroplacental unit including trophoblasts themselves and as such can act in an autocrine manner to induce secretion of CG. Trophoblast production of IL-6 is stimulated by exposure to the pro-inflammatory cytokine, IL-1. Thus, it is feasible that uterine inflammation would lead to altered secretion of CG. Furthermore, women diagnosed with the pregnancy disorder, preeclampsia, have elevated plasma levels of IL-6 and this is associated with elevated levels of CG in circulation. These and other data implicate IL-6 as being involved in trophoblast physiology as well as pathophysiology. The following specific aims are designed to begin to address the hypothesis that IL-6 regulates trophoblast differentiation and secretion of CG. Specific Aim I: Determine the role of IL-6 in regulating trophoblast proliferation and differentiation. Specific Aim II: Investigate IL-6 regulation of gene expression in trophoblasts using gene array technology. Jar choriocarcinoma cells and primary cultures of cytotrophoblasts will be used to address these aims. It is anticipated that data obtained from these experiments will establish IL-6 as being a critical regulator of trophoblast function and will begin to shed light on how IL-6 regulates trophoblast differentiation. The long term goal of these studies is to better understand maternal/fetal cytokine regulation of trophoblast function and ultimately how trophoblast secretory products modulate the maternal immune system to maintain pregnancy.