Pregnancy specific glycoprotein 1 activates transforming growth factor beta

描述(由申请人提供)：怀孕引起了一种独特的免疫学悖论。为了成功怀孕，表达父亲同种异体抗原的胎儿需要避免母体免疫细胞的排斥反应。此外，母亲的免疫系统虽然对胎儿有耐受性，但必须具有抵抗感染的功能。在母胎界面和系统中存在几种机制，它们调节怀孕母亲的免疫状态。这些包括胎盘滋养层细胞分泌的产物，如妊娠特异性糖蛋白(PSGs)。我们的建议集中在PSGs在怀孕期间发挥免疫调节作用的机制上。我们发现本实验室产生的不同形式的重组PSG1与抗炎细胞因子转化生长因子1(TGF-β1)结合。这一观察扩展到从孕妇血清中纯化的天然PSG1。PSG1是否仅仅是转化生长因子-β1的载体，或者它是否可以改变其作用还有待确定。我们推测PSG1与潜伏的转化生长因子-β1结合导致了这一重要细胞因子的激活，除了其抗炎功能外，它还调节着妊娠过程中的许多重要过程，包括滋养层侵袭、内皮细胞功能和细胞外基质沉积。在PSGs被用作治疗剂之前，有必要更好地了解PSGs和转化生长因子-b之间的关系。不同妊娠病理类型(如小于胎龄儿)的孕妇血清中PSGs水平均低于正常水平。最近，我们描述了PSG1除了具有免疫调节功能外，还具有促血管生成功能。PSG1与肝素和硫酸软骨素结合，这种相互作用导致内皮细胞形成毛细血管样结构。与Syndecans或TGF-b相互作用的结构域和结构域中的氨基酸尚未确定，这一信息是设计具有预期效果的基于PSG的治疗干预所必需的。转化生长因子-β的激活是这种多能细胞因子发挥作用的限速步骤。虽然转化生长因子-β的重要性在妊娠期间得到了很好的认识，但它的激活在大多数组织中却知之甚少，包括母胎界面。本项目将确定PSG1的作用机制，并解决一种可能的新的转化生长因子-β1和转化生长因子-β2的激活机制。 公共卫生相关性：异常的胎盘血管生成和母胎交界处的过度炎症可导致不良妊娠结局，包括自然流产、早产、先兆子痫和宫内生长受限。该项目研究妊娠特异性糖蛋白家族在分子水平上的作用机制，该家族在胎盘血管发育和免疫反应调节过程中发挥作用。从这些研究中获得的见解将有助于产生新的治疗策略，用于与怀孕无关的免疫过度激活的情况和某些妊娠并发症。

DESCRIPTION (provided by applicant): Pregnancy poses a unique immunological paradox. For pregnancy to succeed, the fetus, which expresses paternal alloantigens, needs to avoid rejection by maternal immune cells. In addition, the immune system of the mother, while tolerant to the fetus, has to be functional for combating infections. Several mechanisms exist at the maternal-fetal interface and systemically, which regulate the immune status of the pregnant mother. These include secreted products by the trophoblast cells of the placenta, such as pregnancy specific glycoproteins (PSGs). Our proposal centers on the mechanisms by which PSGs exert an immune regulatory role during pregnancy. We found that different form of recombinant PSG1 generated in our laboratory is bound to the anti-inflammatory cytokine transforming growth factor 1 (TGF-b1). This observation was extended to native PSG1, purified from serum of pregnant women. Whether PSG1 is just a carrier of TGF-b1 or it can modify its action remains to be determined. We hypothesize that binding of PSG1 to latent TGF-b1 results in the activation of this important cytokine, which besides its anti-inflammatory function, regulates many important processes during pregnancy including trophoblast invasion, endothelial cell function, and extracellular matrix deposition. A better understanding of the relationship between PSGs and TGF-b is necessary before PSGs can be used as a therapeutic agent. Lower than normal circulating levels of PSGs are found in pregnant serum of women with different pregnancy pathologies such as small for gestational age fetuses. Recently, we described that besides its immune regulatory function, PSG1 is pro-angiogenic. PSG1 binds to the heparin and chondroitin sulfate in syndecans and this interaction results in the formation of capillary-like structures by endothelial cells. The domains, and amino acids within a domain, which interact with syndecans or TGF-b have not been identified and this information is required for a design of a PSG-based therapy intervention with the desired effect. The activation of TGF-b is the rate limiting step in the function of this pluripotent cytokine. While the importance of TGF-b is very well recognize during pregnancy, its activation is very poorly understood in most tissues, including the maternal-fetal interface. This project will define the mechanism of action o PSG1 and address a possible novel mechanism of TGF-b1 and TGF-b2 activation. PUBLIC HEALTH RELEVANCE: Aberrant placental angiogenesis and excessive inflammation at the maternal-fetal interface can lead to adverse pregnancy outcomes including spontaneous abortion, preterm labor, preeclampsia, and intrauterine growth restriction. This project studies the mechanism of action at the molecular level of a family of placental proteins known as pregnancy specific glycoproteins, which play a role in the process of placental vascular development and regulation of the immune response. Insights gained from these studies will help to generate novel therapeutic strategies for conditions with excessive immune activation unrelated to pregnancy and for certain pregnancy complications.