本文選題：母-胎界面 + IL-33��； 參考：《復(fù)旦大學(xué)》2014年碩士論文

【摘要】：妊娠是胚胎(胎兒)在母體內(nèi)生長(zhǎng)發(fā)育的全過程,即從胚胎形成到胎兒及其附屬物從母體排出的全過程。這是一個(gè)由多種因素參與精密調(diào)控的復(fù)雜生理過程。而這其中所蘊(yùn)含的大自然賦予的科學(xué)真理值得深入研究。同時(shí),母-胎界面的生物學(xué)研究對(duì)器官移植和腫瘤研究領(lǐng)域都有著重要的推動(dòng)作用。母-胎界面主要由滋養(yǎng)細(xì)胞、蛻膜基質(zhì)細(xì)胞、蛻膜腺上皮細(xì)胞以及免疫細(xì)胞等多種細(xì)胞及細(xì)胞外環(huán)境中的多種細(xì)胞因子共同構(gòu)成。正常妊娠時(shí)母-胎界面以Th2型免疫占優(yōu)勢(shì),形成免疫耐受的微環(huán)境,以利于同種異體的胚胎在子宮內(nèi)生長(zhǎng)發(fā)育。胎盤的形成是母-胎界面的重要生物學(xué)事件,其成功與否直接影響妊娠的結(jié)局。滋養(yǎng)細(xì)胞增殖與侵襲對(duì)于囊胚植入、胎盤形成,并建立適當(dāng)?shù)哪柑リP(guān)系至關(guān)重要。母-胎界面的滋養(yǎng)細(xì)胞是胚胎種植、胎盤形成過程中一種特殊的上皮細(xì)胞,具有獨(dú)特的高增殖高侵襲的能力。滋養(yǎng)細(xì)胞首先黏附于蛻膜化的子宮內(nèi)膜,而后侵入蛻膜基質(zhì),與母體子宮螺旋小動(dòng)脈接觸,繼而侵入血管腔,沿著血管內(nèi)皮細(xì)胞逆行,向蛻膜深部及子宮肌層的淺1/3-1/2浸潤(rùn),分化并替代血管內(nèi)皮細(xì)胞,形成胎盤的胎兒部分,最終建立母胎循環(huán),促成血管低阻高流量的形態(tài)學(xué)變化,使大量血液供向胎兒,以確保胎兒生長(zhǎng)發(fā)育的需要。以往研究發(fā)現(xiàn)滋養(yǎng)細(xì)胞增殖與侵襲障礙是子癇前期、胎兒宮內(nèi)生長(zhǎng)受限、自然流產(chǎn)等妊娠相關(guān)疾病的主要原因。相反,滋養(yǎng)細(xì)胞的增生和侵襲如果失去了限制,則表現(xiàn)出腫瘤細(xì)胞的特性,導(dǎo)致妊娠滋養(yǎng)細(xì)胞疾病的發(fā)生。滋養(yǎng)細(xì)胞侵入子宮蛻膜受母-胎界面微環(huán)境細(xì)胞與分子間相互作用的調(diào)控。正常情況下,滋養(yǎng)細(xì)胞極少發(fā)生無限增殖和遠(yuǎn)處轉(zhuǎn)移,提示滋養(yǎng)細(xì)胞的黏附和侵襲可能直接或間接受到某些細(xì)胞和細(xì)胞間分子的調(diào)控,使黏附侵襲的促進(jìn)和抑制維持在生理性動(dòng)態(tài)平衡。因此,母-胎界面參與調(diào)控滋養(yǎng)細(xì)胞侵襲力的相關(guān)分子,直接影響胚泡的正常植入和生長(zhǎng)。白細(xì)胞介素(interleukin, IL)是一類參與多種重要生物學(xué)功能調(diào)節(jié)的生物活性分子,參與細(xì)胞間信息的傳遞,激活免疫細(xì)胞,介導(dǎo)T、B淋巴細(xì)胞的活化、增殖與分化,非特異性的調(diào)節(jié)機(jī)體的免疫反應(yīng)并在炎癥反應(yīng)中發(fā)揮重要作用。白細(xì)胞介素-33(IL-33)是IL-1家族的新成員,是炎癥反應(yīng)和免疫偏倚的重要調(diào)節(jié)因子之一,主要誘導(dǎo)Th2型免疫反應(yīng)。IL-33與免疫性疾病、炎癥性疾病、心血管疾病、生殖系統(tǒng)疾病等多種疾病的發(fā)生發(fā)展有關(guān)。IL-33可降低細(xì)胞與細(xì)胞之間鈣粘蛋白的表達(dá),促進(jìn)腫瘤細(xì)胞的脫落、轉(zhuǎn)移。本課題組前期研究已證實(shí)IL-33及其受體ST2在早孕絨毛組織及蛻膜組織中均有表達(dá)。并且研究證實(shí)IL-33可以通過NF-κB和ERK1/2信號(hào)通路上調(diào)CCL2/CCR2促進(jìn)蛻膜基質(zhì)細(xì)胞的增殖和侵襲功能。其他研究還發(fā)現(xiàn)胎盤的IL-33主要來自母-胎界面的巨噬細(xì)胞,通過旁分泌途徑激活滋養(yǎng)細(xì)胞AKT和ERK1/2信號(hào)通路,促進(jìn)滋養(yǎng)細(xì)胞的增殖,對(duì)胎盤的形成具有重要作用。而IL-33對(duì)滋養(yǎng)細(xì)胞的重要生物學(xué)功能——黏附和侵襲是否有影響,目前尚未見報(bào)道。進(jìn)一步解析IL-33在母-胎界面的作用機(jī)制,將有助于闡明生理狀態(tài)下胚泡植入和病理性滋養(yǎng)細(xì)胞疾病發(fā)生的機(jī)理,對(duì)治療復(fù)發(fā)性流產(chǎn)、子癇前期、胎兒宮內(nèi)生長(zhǎng)受限及滋養(yǎng)細(xì)胞相關(guān)疾病等亦具有潛在的臨床價(jià)值。本課題在以往研究的基礎(chǔ)上,進(jìn)一步關(guān)注IL-33對(duì)滋養(yǎng)細(xì)胞黏附和侵襲功能的影響,并解析IL-33在母-胎界面對(duì)滋養(yǎng)細(xì)胞生物學(xué)功能調(diào)控的可能機(jī)制。第一部分IL-33及其受體ST2在母-胎界面的表達(dá)目的：分析孕晚期IL-33及其受體ST2在母-胎界面的表達(dá)情況,了解IL-33及受體ST2在母-胎界面的表達(dá)特征。方法：選取2013年在復(fù)旦大學(xué)附屬婦產(chǎn)科醫(yī)院正規(guī)產(chǎn)檢并足月妊娠行選擇性剖宮產(chǎn)的正常孕婦8例。于剖宮產(chǎn)手術(shù)時(shí)收集新鮮胎盤組織。石蠟包埋切片。采用免疫組織化學(xué)技術(shù),檢測(cè)母-胎界面IL-33及其受體ST2的表達(dá)情況。結(jié)果：正常足月妊娠母-胎界面共表達(dá)細(xì)胞因子IL-33及其受體ST2。免疫組織化學(xué)結(jié)果顯示正常足月妊娠分娩的胎盤組織中可見IL-33及ST2表達(dá),IL-33主要表達(dá)于滋養(yǎng)細(xì)胞的細(xì)胞核中,ST2則主要表達(dá)于滋養(yǎng)細(xì)胞和基質(zhì)細(xì)胞,以胞膜胞漿表達(dá)為主。結(jié)論：IL-33及其受體ST2共表達(dá)于母-胎界面。提示：IL-33/ST2軸在正常妊娠的胎盤形成及功能維持中可能發(fā)揮作用。第二部分IL-33對(duì)滋養(yǎng)細(xì)胞黏附和侵襲功能的影響目的：明確滋養(yǎng)細(xì)胞系細(xì)胞表面IL-33受體ST2表達(dá)情況；探討IL-33對(duì)滋養(yǎng)細(xì)胞黏附功能和侵襲功能的調(diào)控作用。方法：采用流式細(xì)胞術(shù)檢測(cè)滋養(yǎng)細(xì)胞系JEG-3、JAR、BeWo、HTR-8細(xì)胞表面ST2的表達(dá)情況。利用多基質(zhì)黏附試劑盒檢測(cè)不同濃度IL-33作用48小時(shí)后,滋養(yǎng)細(xì)胞對(duì)基質(zhì)Fibronectin、Laminin Ⅰ、Fibrinogen、Collagen Ⅰ和CollagenⅣ的黏附能力的改變。通過建立Trans well體系,檢測(cè)不同濃度IL-33作用48小時(shí)后滋養(yǎng)細(xì)胞的侵襲能力的改變。結(jié)果：流式細(xì)胞術(shù)檢測(cè)結(jié)果顯示JAR、BeWo、JEG-3和HTR8細(xì)胞均表達(dá)IL-33受體ST2,其中以BeWo細(xì)胞表達(dá)最高,而HTR8細(xì)胞最低。選擇對(duì)子宮內(nèi)膜黏附和侵襲能力最高的JEG-3細(xì)胞進(jìn)行后續(xù)實(shí)驗(yàn)。黏附實(shí)驗(yàn)結(jié)果顯示,外源性重組人IL-33(rhIL-33)作用JEG-3細(xì)胞48小時(shí)后,JEG-3細(xì)胞對(duì)基質(zhì)Fibronectin、 Laminin Ⅰ、Collagen Ⅳ和Fibrinogen的黏附能力減弱,且差異具有統(tǒng)計(jì)學(xué)意義。IL-33對(duì)滋養(yǎng)細(xì)胞系JEG-3細(xì)胞與基質(zhì)Collagen Ⅰ的黏附能力沒有明顯影響。侵襲結(jié)果顯示,rhIL-33作用JEG-3細(xì)胞48小時(shí)后,JEG-3細(xì)胞對(duì)Matrigel的穿透能力下降即JEG-3細(xì)胞的侵襲力減弱。結(jié)論：外源性重組人IL-33明顯抑制滋養(yǎng)細(xì)胞對(duì)基質(zhì)Fibronectin、Laminin Ⅰ、 Fibrinogen和Collagen Ⅳ的黏附能力,并且抑制滋養(yǎng)細(xì)胞的侵襲功能。此部分結(jié)果提示在母-胎界面中,IL-33通過調(diào)節(jié)滋養(yǎng)細(xì)胞的黏附和侵襲能力,有利于控制滋養(yǎng)細(xì)胞對(duì)母體組織的侵入深度,防止過度侵襲,維持母-胎界面生理性動(dòng)態(tài)平衡,有利于正常胎盤的形成,從而有助于正常妊娠的維持。第三部分IL-33對(duì)滋養(yǎng)細(xì)胞表面黏附分子表達(dá)的調(diào)節(jié)目的：探討IL-33調(diào)節(jié)滋養(yǎng)細(xì)胞黏附能力的機(jī)制,即IL-33通過何種方式實(shí)現(xiàn)對(duì)滋養(yǎng)細(xì)胞黏附功能的調(diào)控。方法：以滋養(yǎng)細(xì)胞系JEG-3細(xì)胞為研究對(duì)象,重組人IL-33作用48小時(shí)后,采用流式細(xì)胞術(shù)分析JEG-3細(xì)胞表面黏附和侵襲相關(guān)分子(integrin α3β1、integrin α4β1、integrin α5β1、integrin α6β1、integrin αvβ3、E-cadherin、CD62L、CD44)的表達(dá)變化。結(jié)果：外源性重組人的IL-33降低滋養(yǎng)細(xì)胞系JEG-3細(xì)胞表面黏附侵襲相關(guān)分子的表達(dá)。外源性加入重組人IL-33培養(yǎng)JEG-3細(xì)胞48小時(shí)后,流式細(xì)胞術(shù)分析滋養(yǎng)細(xì)胞JEG-3細(xì)胞表面黏附侵襲相關(guān)分子表達(dá)的情況。結(jié)果顯示,滋養(yǎng)細(xì)胞系JEG-3細(xì)胞表面高表達(dá)inte grin α3β1、integrin α5β1、integrin α6β1、E-cadherin,低表達(dá)integrin α4β1、CD62L,不表達(dá)CD44、integrin αvβ3分子。在細(xì)胞培養(yǎng)液中加入rhIL-33后,與對(duì)照組相比,實(shí)驗(yàn)組integrin α4β1、CD62L的表達(dá)下調(diào),且差異具有統(tǒng)計(jì)學(xué)意義。其他分子表達(dá)變化無顯著性差異。結(jié)論：IL-33通過下調(diào)滋養(yǎng)細(xì)胞表面的黏附侵襲相關(guān)分子的表達(dá),實(shí)現(xiàn)對(duì)滋養(yǎng)細(xì)胞黏附和侵襲功能的調(diào)節(jié)。綜上所述,本研究發(fā)現(xiàn)妊娠母-胎界面滋養(yǎng)細(xì)胞共表達(dá)IL-33及其受體ST2,提示IL-33/ST2可能通過自分泌或者旁分泌方式參與滋養(yǎng)細(xì)胞生物學(xué)功能的調(diào)節(jié)。以表達(dá)受體ST2且對(duì)子宮內(nèi)膜黏附和侵襲力較強(qiáng)的滋養(yǎng)細(xì)胞系JEG-3細(xì)胞代替母-胎界面滋養(yǎng)細(xì)胞進(jìn)行本研究。結(jié)果顯示,IL-33可能通過下調(diào)細(xì)胞表面黏附侵襲相關(guān)分子integrin α4β1、CD62L的表達(dá),從而抑制滋養(yǎng)細(xì)胞黏附和侵襲功能,參與滋養(yǎng)細(xì)胞生物學(xué)行為的精密調(diào)控。本研究為完善滋養(yǎng)細(xì)胞黏附和侵襲調(diào)控機(jī)制,及臨床治療反復(fù)自然流產(chǎn)、妊娠滋養(yǎng)細(xì)胞疾病等妊娠相關(guān)疾病提供了新策略與新思路。
[Abstract]:Pregnancy is the whole process of growth and development of the embryo (fetus) in the mother body, from embryo formation to the whole process of the fetus and its appendages discharged from the mother body. This is a complex physiological process involved in a variety of factors, and the scientific truth endowed by nature deserves in-depth study. Studies have played an important role in the field of organ transplantation and cancer research. The mother fetal interface is mainly composed of a variety of cells, such as trophoblastic cells, decidual stromal cells, decidual epithelial cells and immune cells, and a variety of cytokines in the extracellular environment. The mother fetal interface is dominated by Th2 type immunization during normal pregnancy. The microenvironment of immune tolerance is beneficial to the growth and development of allogenic embryos in the uterus. The formation of the placenta is an important biological event of the mother fetal interface. Its success directly affects the outcome of pregnancy. The proliferation and invasion of trophoblastic cells are essential to the implantation of blastocysts, the formation of placenta, and the establishment of a proper maternal fetal relationship. Trophoblast is a special epithelial cell in the process of embryo cultivation. It has a unique high proliferation and high invasion ability. The trophoblastic cells first adhered to the deciduated endometrium and then intruded into the decidua matrix, exposed to the uterine spiral arterioles of the mother's uterus, then intruded into the blood tube cavity, and followed the vascular endothelial cells retrograde to the decidua. The shallow 1/3-1/2 infiltration of the Ministry and the myometrium of the uterus, differentiating and replacing the vascular endothelial cells, forming the fetal part of the placenta, finally establishing the fetal cycle, contributing to the morphological changes of the low resistance and high flow of blood vessels, making a large amount of blood supply to the fetus to ensure the growth and development of the fetus. The main causes of pregnancy related diseases such as fetal intrauterine growth restriction and spontaneous abortion. On the contrary, if the proliferation and invasion of the trophoblastic cells are lost, it shows the characteristics of the tumor cells and leads to the occurrence of gestational trophoblastic diseases. Regulation. Under normal conditions, the trophoblastic cells rarely occur unlimited proliferation and distant metastasis, suggesting that the adhesion and invasion of trophoblast may directly or indirectly accept the regulation of certain cells and intercellular molecules, so that the promotion and inhibition of adhesion invasion are maintained in the physiological dynamic balance. Therefore, the mother fetal interface participates in the regulation of the invasiveness of trophoblast cells. Related molecules, directly affecting the normal implantation and growth of the blastocyst. Interleukin (IL) is a class of bioactive molecules involved in a variety of important biological functions. It participates in the transmission of information between cells, activates the immune cells, mediates the activation, proliferation and differentiation of T, B lymphocytes, and the nonspecific immune response to the body. Interleukin -33 (IL-33), a new member of the IL-1 family, is one of the important regulators of the inflammatory response and immune bias. The main inducement of the Th2 type immune response.IL-33 is related to the development of a variety of diseases such as immune diseases, inflammatory diseases, cardiovascular diseases, and biological diseases. Reducing the expression of cadherin between cells and cells and promoting the Exfoliative and metastasis of tumor cells. Previous studies have confirmed that IL-33 and its receptor ST2 are expressed in the villi and decidua tissues of early pregnancy. And it has been proved that IL-33 can promote the proliferation of decidual stromal cells through the NF- kappa B and ERK1/2 signaling pathways. Other studies have also found that the IL-33 of the placenta mainly comes from the macrophages of the mother fetal interface, activating the AKT and ERK1/2 signaling pathways through paracrine pathways, promoting the proliferation of trophoblastic cells and the important role of the placenta, and the important biological function of IL-33 to the trophoblastic cells: whether or not the adhesion and invasion of trophoblast are available. No reports have been reported at present. Further analysis of the mechanism of IL-33 in the mother fetal interface will help to elucidate the mechanism of blastocyst implantation and pathological trophoblastic disease in physiological state. It is also of potential clinical value for the treatment of recurrent abortion, preeclampsia, fetal intrauterine growth restriction and trophoblast related diseases. On the basis of previous studies, we further pay attention to the effect of IL-33 on the adhesion and invasion of trophoblastic cells, and analyze the possible mechanism of IL-33 in the control of the biological function of trophoblast in the mother fetal boundary. The first part of the expression of IL-33 and its receptor ST2 at the mother fetal interface: analysis of IL-33 and its receptor ST2 at the mother fetal interface in the late pregnancy To understand the expression of IL-33 and receptor ST2 at the mother fetal interface. Methods: 8 normal pregnant women who were selected in 2013 at the Department of Obstetrics and Gynecology, affiliated to the Fudan University, were selected for regular pregnancy and full term pregnancy. The fresh placenta tissue was collected during cesarean section. The paraffin embedded section was examined by immunohistochemistry. The expression of IL-33 and its receptor ST2 at the mother fetal interface. Results: the immunohistochemical results of the co expression of cytokine IL-33 and its receptor ST2. in the mother fetal interface of normal term pregnancy showed that the expression of IL-33 and ST2 was found in the placental tissue of normal term pregnancy, and IL-33 was mainly expressed in the nucleus of trophoblastic cells and ST2 was mainly expressed in the trophoblast. IL-33 and its receptor ST2 are co expressed in the mother fetal interface. It is suggested that the IL-33/ST2 axis may play a role in the formation and function maintenance of placenta in normal pregnancy. Second the effect of part IL-33 on the adhesion and invasion of trophoblastic cells: the clear cell line of the trophoblastic cell line The expression of IL-33 receptor ST2 and the regulation of IL-33 on the adhesion and invasion of trophoblastic cells. Methods: flow cytometry was used to detect the expression of ST2 in the trophoblastic line JEG-3, JAR, BeWo, HTR-8 cells. 48 hours after the detection of different concentration IL-33 activity by multi matrix adhesion kit, the trophoblastic cell to matrix Fibr. Changes in the adhesion of onectin, Laminin I, Fibrinogen, Collagen I and Collagen IV. By establishing a Trans well system, the invasion ability of the trophoblastic cells was detected after 48 hours of action of different concentrations of IL-33. Results: the results of flow cytometry showed that JAR, BeWo, JEG-3, and HTR8 cells were all expressed. The cell expression was the highest and the HTR8 cell was the lowest. The JEG-3 cells with the highest adhesion and invasion ability of the endometrium were selected for follow-up experiments. The adhesion test showed that the adhesion ability of JEG-3 cells to matrix Fibronectin, Laminin I, Collagen IV and Fibrinogen was weakened after 48 hours of exogenous recombinant human IL-33 (rhIL-33). The difference had statistical significance.IL-33 on the adhesion ability of the trophoblast line JEG-3 cells to the matrix Collagen I. The invasion results showed that the penetration ability of JEG-3 cells to Matrigel decreased after 48 hours of rhIL-33 action, that is, the invasion ability of JEG-3 cells was weakened. Cell adhesion to matrix Fibronectin, Laminin I, Fibrinogen and Collagen IV, and inhibition of the invasion function of trophoblastic cells. This part suggests that in the mother fetal interface, IL-33 can control the invasion depth of the trophoblastic cells by regulating the adhesion and invasion of trophoblastic cells, preventing excessive invasion and maintenance. The physiological dynamic balance of mother fetal interface is beneficial to the formation of normal placenta and helps to maintain normal pregnancy. Third part IL-33 regulates the expression of adhesion molecules on the surface of trophoblastic cells: the mechanism of IL-33 regulating the adhesion of trophoblastic cells, that is, how IL-33 regulates the adhesion function of trophoblastic cells. Methods: the expression changes of JEG-3 cell adhesion and invasion related molecules (integrin alpha 3 beta 1, integrin alpha 4 beta 1, integrin a 5 beta 1, integrin a 6 beta 1, integrin a V beta 3, E-cadherin, CD62L, CD44) were analyzed by flow cytometry after 48 hours of recombinant human IL-33. Group human IL-33 reduced the expression of adhesion and invasion related molecules on the surface of trophoblast cell line JEG-3. After exogenous IL-33 was added to JEG-3 cells for 48 hours, flow cytometry was used to analyze the expression of adhesion and invasion related molecules on the surface of trophoblast JEG-3 cells. The results showed that the surface of the trophoblastic line JEG-3 cells expressed inte grin on the surface of the cell line. Alpha 3 beta 1, integrin alpha 5 beta 1, integrin alpha 6 beta 1, E-cadherin, low expression of integrin alpha 4 beta 1, CD62L, did not express CD44, integrin alpha v beta 3. After adding rhIL-33 to the cell culture solution, the expression of integrin alpha 4 beta 1, CD62L was down, and the difference was of no significant difference between the other molecules. IL-33 can regulate the adhesion and invasion function of trophoblastic cells by lowering the expression of adhesion and invasion related molecules on the surface of trophoblastic cells. To sum up, this study found that the pregnancy mother fetal interface trophoblastic cells co expressed IL-33 and its receptor ST2, suggesting that IL-33/ST2 may participate in trophoblast through autocrine or paracrine ways. The regulation of physical function. This study was conducted to express receptor ST2 and to replace the mother fetal interface trophoblast cell line JEG-3 cells with strong endometrium adhesion and invasiveness. The results showed that IL-33 may inhibit the adhesion and invasion of trophoblastic cells by regulating the adhesion and invasion of integrin alpha 4 beta 1, the expression of CD62L. This study provides new strategies and new ideas for improving the regulation mechanism of trophoblast adhesion and invasion, and the clinical treatment of recurrent spontaneous abortion, gestational trophoblastic disease and other pregnancy related diseases.

【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R714

【共引文獻(xiàn)】

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2 邱艷;趙凌杰;;白介素33在類風(fēng)濕關(guān)節(jié)炎中的研究進(jìn)展[J];安徽醫(yī)藥;2014年07期

3 劉偉;朱曉勇;金莉萍;;IL-33及其受體ST2的研究進(jìn)展[J];現(xiàn)代免疫學(xué);2014年05期

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2 郭治;IL-33參與支氣管哮喘氣道重塑的機(jī)制研究[D];山東大學(xué);2014年

3 湯賢英;中性粒細(xì)胞通過促進(jìn)IL-33成熟而參與類風(fēng)濕性關(guān)節(jié)炎發(fā)生和進(jìn)程[D];華中科技大學(xué);2014年

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3 洪春梅;類風(fēng)濕關(guān)節(jié)炎患者IL-27及其受體的表達(dá)與IL-17、IL-33相關(guān)性的研究[D];福建醫(yī)科大學(xué);2014年

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