CYTOKINE REGULATION OF TROPHOBLAST FUNCTION

在人类和灵长类动物中，滋养层分泌的绒毛膜促性腺激素（CG）作为母体识别妊娠的胚胎信号。CG是由α亚基和不同的CG β亚基组成的异二聚体糖蛋白激素。CG的表达发生在受精后几天，胎盘细胞滋养层细胞分化为合体滋养层细胞。CG的缺乏导致新的月经周期的开始。据报道，细胞因子在调节CG分泌中起作用，并被假定调节细胞滋养层分化。在这些细胞因子中，白细胞介素-6（IL-6）和白血病抑制因子（LIF;同一细胞因子家族的成员）已被证明在妊娠期间具有重要作用。LIF在胚泡植入时由子宫产生，并且可以在体外刺激滋养外胚层增殖。IL-6由子宫胎盘单位内外的多种细胞类型分泌，包括滋养层细胞本身，因此可以自分泌方式诱导CG分泌。通过暴露于促炎细胞因子IL-1刺激滋养层产生IL-6。因此，子宫炎症可能导致CG分泌改变。此外，被诊断患有妊娠障碍、先兆子痫的妇女具有升高的IL-6血浆水平，并且这与循环中升高的CG水平相关。这些和其他数据暗示IL-6参与滋养层生理学以及病理生理学。以下具体目的旨在开始解决IL-6调节滋养层分化和CG分泌的假设。特定目的I：确定IL-6在调节滋养层细胞增殖和分化中的作用。具体目的二：利用基因芯片技术研究IL-6对滋养层细胞基因表达的调控。罐状绒毛膜癌细胞和原代培养的细胞滋养层细胞将用于解决这些目标。预期从这些实验获得的数据将确立IL-6作为滋养层功能的关键调节剂，并且将开始阐明IL-6如何调节滋养层分化。这些研究的长期目标是更好地了解母体/胎儿滋养层功能的细胞因子调节，并最终了解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.