INTERLEUKIN-1 IN HUMAN IMPLANTATION

植入生物学是最重要但最不为人所知的 妇女的健康问题。 人类胚胎植入失败或有缺陷 植入导致随后的妊娠丢失是一个主要的临床 人类生殖生物学的问题。 美国9对夫妇之一 据估计，只有三分之一的美国人是非自愿无子女的。 潜在的生育周期导致一个孩子大约有30%的 胚胎从未达到子宫着床阶段，再增加30% 其植入但形态异常且不能存活。 更 最近，对人绒毛膜促性腺激素（hCG）的敏感测定已经 有证据表明，22%的hCG检测妊娠失败， 存活足够长的时间以被临床识别。因此， 临床上未识别的植入失败率很高。 此外，本发明还提供了一种方法， 临床诊断的怀孕自然流产率为15-25%。 最近，几个免疫学病因妊娠浪费和习惯性 有人提出堕胎，但实际上对堕胎的可能性知之甚少。 妊娠丢失免疫发病机制 在本提案中，我们将 研究IL-1系统--IL -1 β，其受体 拮抗剂--在人类植入过程中至关重要。 我们的第一 目的：研究人IL-1受体I型（IL-1 R tI）的调控 子宫内膜间质细胞和腺细胞培养。 这些研究将 检查IL-1 β和其他细胞因子和生长因子的能力， 调节和上调子宫内膜IL-1 RTI的蛋白和RNA表达。 此外，由细胞分泌的生长因子和细胞因子的能力 将使用以下方法评估人胚胎调节子宫内膜IL-IR tI水平 人类胚胎条件培养基。 第二个目标将考察 IL-1 β调节纤溶酶原激活物系统作为一个重要的 子宫内膜反应允许胚胎侵入的机制， 置入 本研究的第三个目的是检查子宫内膜 IL-1受体拮抗剂（IL-1 R）的定位和体外调节 人子宫内膜腺细胞和间质细胞中1 ra）mRNA和蛋白的表达 培养物和IL-1 ra消除IL-1上调的能力 IL-1 β和其他生长因子。 第四个目标是学习 通过检测IL-1 ra对着床能力， 当注入PMSG/hCG时干扰着床和妊娠 刺激并交配小鼠。 我们的假设是IL-1的适当激活和上调， IL-1 β受体和其他胚胎产生的细胞因子， 对人类胚胎成功植入至关重要。 一个推论是， 1 ra能够干扰成功植入。 阐明 细胞因子介导的胚胎与子宫内膜的关系 在早期植入过程中， 临床上重要的与着床有关的不孕症 失败和习惯性流产;这些知识将扩大我们的 了解早期着床事件，并有可能 临床应用于妊娠丢失综合征。

Implantation biology is one of the most important yet least understood women's health issues. Failure of the human embryo to implant or faulty implantation resulting in subsequent pregnancy loss is a major clinical problem in human reproductive biology. One of 9 couples in the United States is involuntarily childless and it is estimated that only 1/3 of potentially fertile cycles result in a child with approximately 30% of embryos never reaching the stage of uterine implantation ad another 30% which implant but are morphologically abnormal and non-viable. More recently, sensitive assays for human chorionic gonadotropin (hCG) have documented that 22% of all pregnancies detected by hCG assay fail to survive long enough to be clinically recognized. Thus, the incidence of clinically unrecognized implantation failure is high. In addition, spontaneous abortion rates are 15-25% for clinically diagnosed pregnancies. Recently, several immunologic etiologies for pregnancy wastage and habitual abortion have been proposed but little is actually known about the possible immunologic pathogenesis of pregnancy wastage. In this proposal, we will investigate the hypothesis that the IL-1 system --IL - 1beta, its receptor antagonist -- are critical in the process of human implantation. Our first goal is to study the regulation of IL-1 receptor type I (IL-1R tI) in human endometrial stromal and glandular cell cultures. These studies will examine the ability of IL-1beta and other cytokines and growth factors to modulate and upregulate protein and RNA expression of endometrial IL-IR tI. In addition, the ability of growth factors and cytokines secreted by the human embryo to modulate endometrial IL-IR tI levels will be assessed using human embryo-conditioned media. The second goal will examine the ability of IL-1beta to modulate the plasminogen activator system as an important mechanism of endometrial response permitting embryonic invasion and implantation. The third goal of this study is to examine the endometrial localization and in vitro regulation of both IL-1 receptor antagonist (IL- 1ra) mRNA and protein in human endometrial glandular and stromal cell cultures and the ability of IL-1ra to ablate upregulation of the IL-1 receptor by IL-Ibeta and other growth factors. The fourth goal is to study the in vivo effect of Il-1ra on implantation by examining its ability to interfere with implantation and pregnancy when injected into PMSG/hCG stimulated and mated mice. Our hypothesis is that appropriate activation and upregulation of the IL-1 receptor by IL-1beta and by other embryonically generated cytokines is critical to successful human embryo implantation. A corollary is that IL- 1ra is capable of interfering with successful implantation. Elucidation of the cytokine mediated relationship between the embryo and endometrium during early implantation is critical to the understanding of the clinically important entities of infertility related to implantation failure and habitual abortion; such knowledge will broaden our understanding of the events of early implantation and has potential clinical application in syndromes of pregnancy wastage.