前列腺素对妊娠子宫肌炎性因子生成和收缩相关蛋白表达的调节作用
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摘要
胚胎的植入，妊娠的维持以及分娩的发生等一系列过程都与母胎界面免疫反应密切相关。研究表明，分娩启动与宫内局部炎症微环境的改变有关，炎性因子可调控子宫肌组织收缩相关蛋白等表达，而使子宫肌收缩活性的发生改变，从而启动分娩。但是子宫局部炎症微环境的调控机制，目前尚不清楚。前列腺素F2α一直被认为是有效的宫缩激动剂，但应用在临床引产却通常需要数小时的延迟作用时间，提示了其对子宫肌收缩力的调控机制可能先参与了子宫肌的激活过程，而后再刺激子宫产生规律收缩。有研究报道分娩启动前孕妇羊水中PGs水平显著升高，且分娩启动后并没有进一步升高，这提示了前列腺素很可能参与了分娩启动前子宫肌的激活，因此在本课题的第一部分，我们以原代培养子宫平滑肌细胞为研究模型，研究了子宫内二种主要的前列腺素——PGF2α及PGE2是否调节妊娠子宫肌细胞炎性因子的生成，进而影响宫内炎症微环境的改变。
妊娠期间子宫肌的功能状态呈现动态变化，即在大部分时间内其处于静息，在妊娠末期时出现规律性的收缩。子宫肌从静息转化为收缩是与子宫肌组织与收缩相关蛋白表达水平有关。前列腺素是否具有直接调节子宫肌收缩相关表达的作用，尚未见相关报道。因此，本课题的第二部分，我们对以PTGS-2，OTR，CX43以及PTGFR四种蛋白作为UAPs家族的代表，研究了PGF2α及PGE2是否可能通过调节这些蛋白的表达而参与了子宫肌的激活过程。
此外，转录因子与其下游靶基因的表达密切相关，其直接结合于靶基因启动子区域，从而影响了靶基因的转录过程。锌指E盒结合同源盒蛋白（ZEB）作为一转录抑制因子，已被证实参与了收缩相关蛋白CX43，OTR等的转录调控。那么在分娩启动前期，是否收到前列腺素的调控目前还未见明确报道。
实验结果如下：
一、PGs通过不同受体对妊娠子宫平滑肌细胞上炎症因子生成的调节作用
1.在分娩启动前期子宫肌激活的过程中，PGF2α可刺激促炎因子IL-6，IL-1β，趋化因子IL-8，MCP-1，以及生长因子VEGF的表达上调；但抑制了TNFα的生成。
2. PGF2α-PTGFR激活的胞内信号转导通路，主要由PLC-PKC通路上调子宫平滑肌细胞中IL-6，IL-1β, IL-8, MCP-1，VEGF的生成，同时抑制了TNFα的生成；而Calcineurin-NFAT通路的激活则介导了对MCP-1以及TNFα的生成；P38-STATs通路主要参与了对MCP-1生成的调节，PI3K通路则可能调节MCP-1和VEGF的生成。
3. PGE2通过EP1/3上调IL-6，VEGF，TNF 的生成，但同时减少了IL-1β的生成；通过EP2上调IL-6，IL-8，IL-1β以及VEGF的生成，在低浓度时促进TNFα的生成，在高浓度时抑制其生成；通过EP4主要下调了VEGF的生成，同时上调IL-1β以及TNFα的生成。PGE2对趋化因子MCP-1并未见明显的调节作用。
4. PGF2α以及PGE2均参与分娩前期炎症相关因子的生成，一方面通过促进促炎因子的生成创造了分娩启动前期子宫局部炎症微环境的建立，同时刺激子宫平滑肌分泌的趋化因子对于白细胞向宫内的招募富集，进一步扩大炎症反应的进行提供了有利条件。
二、PGs通过不同受体对妊娠子宫平滑肌细胞上子宫收缩相关蛋白表达的调节作用
1.前列腺素F2α通过激活Gq蛋白，经胞内一系列信号分子P38,PI3K和PLC-β-PKC等的传递，介导了对子宫收缩相关蛋白CX43，PTGS-2以及OTR表达的上调作用，而同时以负反馈调节的方式降低了自身受体的表达。
2. PGE2则分别通过收缩性受体EP1/3上调了CX43，PTGS-2，OTR以及PTGFR的表达，而舒张性受体EP2则通过抑制OTR以及PTGFR的表达降低子宫平滑肌对催产素和前列腺素等宫缩剂的敏感性。通过两类受体亚型的相互协调作用，完成对收缩相关蛋白的表达的精细调节。
三、PGs通过不同受体对妊娠子宫平滑肌细胞上转录因子ZEBs的调节作用
1. PGF2α可剂量依赖性减少ZEB两种亚型蛋白水平的表达。
2．PGE2主要是发挥着下调ZEB1的调节作用，但是其通过EP1/3可上调ZEB1和ZEB2；通过EP2和EP4下调ZEB1以及ZEB2的蛋白表达。
结论：
本研究表明，临近分娩时孕妇羊水中高表达的前列腺素PGF2α及PGE2在子宫肌局部通过自分泌或旁分泌的方式，一方面可通过促进炎症相关的促炎因子及子的表达，参与构建宫内局部炎症微环境，同时也通过上调VEGF的表达改变子宫肌细胞的通透性，刺激宫内趋化因子的表达，从而为炎症反应的扩大提供有利条件。另一方面，通过上调子宫收缩相关蛋白的表达来直接激活子宫肌的收缩状态，为分娩的顺利进行做好准备。
Numerous physiological processes, like implantation, pregnancy maintaince and thetrigger of parturtiton, have close relationship with maternal immune system. Evidenceindicated that the establishment of inflammatory environment in intrauterine organscontributes to the initiation of parturition. The cytokines and chemokines activate themyometrium contractile ability changes via modulating contraction-related fators, andfurther more initate the parturition of labor. However there is no definite conclusion aboutthe regulation mechanism of inflammation factors during pregnancy and parturition.Considering as the most powerful contractile agonist of myometrium, PGs was reported todelay the stimulatory effect in clinical application as the drug induced labor. Thus thisfinding indicated that the regulatory mechanism of PGs on myometrium contractility mightgo through the uterus activation process in the early stage of parturition initiation and latersitmulates the regular contration in uterus. Reports demonstrated that the level of PGsdetected in amion fluid before parturition arised significantly which possibly contribute tothe uterine activation process during the early parturition. Without clarified explainationabout the hypothesis, we studied whether PGF2α and PGE2modulate the inflammation-related factors expression during normal pregnancy based on the cultured myometrialsmooth muscle cells.
The contractility of uterus is influenced by changes of hormones level, expression ofcontractile proteins and other factors. The alteration of contractile protein family onexpression and function represents the contract ability of uterus. PGs have been discoveredinvolved in the regulation of some contractile proteins. However more studies are requiredfor the possible activated signal pathway mechanism triggered by PGF2α and PGE2inmyometrial cells. Here in our study, PTGS-2, CX43, OTR and PTGFR are taken as fourproxies for the uterine activation protein family (UAPs).
In the third part, the role of transcriptional factor，Zinc E box binding homeobox,(ZEB) was taken into consideration that particicpated in the effect of PGs on uterineactivation process. Evidences indicated that ZEBs could directly bind to the promoters ofOTR and CX43and futher regulated their protein abundance. Therefore, we focused onwhether ZEBs medicatd partially the regulation of PGs on uterine activation proteinsexpression. Main results:
1. Regulation of inflammatory cytokines expression mediated by prostaglandinsvia different receptors
1) In the uterine activation process, PGF2α stimulated the outputs of pro-inflammatory cytokines, such as IL-6, IL-1β, the outputs of chemokines, like IL-8, MCP-1,and growth factor VEGF output, while decreased the output of cytokine TNFα.
2) PGF2α receptor, PTGFR, trigger the intracellular multiple signal pathways toregulate the outputs of cytokines and chemokines. The outputs of IL-6，IL-1β, IL-8,MCP-1，VEGF and TNFα were modulated by PLC-β-PKC pathway. While the activationof Calcineurin-NFAT pathway involved in the regulation on MCP-1and TNFα outputs.The output of MCP-1was also mediated by P38-STATs pathway, while the PI3K activationparticipated in the regulation of MCP-1and VEGF outputs.
3) PGE2via EP1/3up-regulated the outputs of IL-6, VEGF, TNFα, while decreasedIL-1β output. EP2agonist stimulated the outputs of IL-6, IL-8, IL-1β, and VEGF dose-dependently. But there exist the dual effect of EP2mediating the output of TNFα, i.e itshowed the stimulatory effect at the low concentration while decreased TNFα output at thehigh concenctration. And EP4agonist mainly down-regulated VEGF output and increasedIL-1β and TNFα outputs. Compared withhere is no significant effect on chemokine MCP-1output by PGE2.
2. Regulation of uterine activation proteins expression mediated byprostaglandins via different receptors
1) PGF2α via its Gq protein-coupled receptor PTGFR, activated intracellular PLCβ-PKC pathway and other signal factors to up-regulate the expression of uterine activationproteins, such as CX43, PTGS-2, OTR. Meanwhile PGF2α showed the negative feedbackmodulation on its own receptor expression.
2) The contractile receptors EP1/3of PGE2mediated the stimulatory effect on UAPsexpression. While the relaxant receptor EP2and EP4mainly reduced the sensitivity ofmyometrial cells on oxytocin and PGs by down-regulating their receptor expression.Therefore PGE2achieved the subtle regulation on the uterine activation proteinsabundance by the balanced coordination among receptors.
3. Regulation of transcript factor--ZEBs expression mediated by prostaglandinsvia different receptors
1) PGF2α downregulated ZEB1and ZEB2protein abundances in pregnant myomtrial cells.
2) PGE2mainly decreased ZEB1expression while ZEB2abundance remained at thesimilar level. However the contractile receptor EP1/3specific agonist increased ZEBsexpression while EP2and EP4agonists downregulated their abundances.Conclusion
In concluation, our study demonstrated that the arising level of PGF2α and PGE2inamnion fluid of pregnant women, took act on myometrium via autocrine or paracrine mean.On one hand, PGs contributed the micro inflammatory environment in intrauterine organsby promoting inflammation-related cytokines and chemokines expression. Meanwhile theupregulated VEGF level may contribute to the permeability of myometrial cells allowingmigration of leukocytes to uterus. On the other hand, the up-regulation of uterus contractileproteins can activate myometrium and prepare for the parturition.
妊娠期间子宫肌的功能状态呈现动态变化，即在大部分时间内其处于静息，在妊娠末期时出现规律性的收缩。子宫肌从静息转化为收缩是与子宫肌组织与收缩相关蛋白表达水平有关。前列腺素是否具有直接调节子宫肌收缩相关表达的作用，尚未见相关报道。因此，本课题的第二部分，我们对以PTGS-2，OTR，CX43以及PTGFR四种蛋白作为UAPs家族的代表，研究了PGF2α及PGE2是否可能通过调节这些蛋白的表达而参与了子宫肌的激活过程。
此外，转录因子与其下游靶基因的表达密切相关，其直接结合于靶基因启动子区域，从而影响了靶基因的转录过程。锌指E盒结合同源盒蛋白（ZEB）作为一转录抑制因子，已被证实参与了收缩相关蛋白CX43，OTR等的转录调控。那么在分娩启动前期，是否收到前列腺素的调控目前还未见明确报道。
实验结果如下：
一、PGs通过不同受体对妊娠子宫平滑肌细胞上炎症因子生成的调节作用
1.在分娩启动前期子宫肌激活的过程中，PGF2α可刺激促炎因子IL-6，IL-1β，趋化因子IL-8，MCP-1，以及生长因子VEGF的表达上调；但抑制了TNFα的生成。
2. PGF2α-PTGFR激活的胞内信号转导通路，主要由PLC-PKC通路上调子宫平滑肌细胞中IL-6，IL-1β, IL-8, MCP-1，VEGF的生成，同时抑制了TNFα的生成；而Calcineurin-NFAT通路的激活则介导了对MCP-1以及TNFα的生成；P38-STATs通路主要参与了对MCP-1生成的调节，PI3K通路则可能调节MCP-1和VEGF的生成。
3. PGE2通过EP1/3上调IL-6，VEGF，TNF 的生成，但同时减少了IL-1β的生成；通过EP2上调IL-6，IL-8，IL-1β以及VEGF的生成，在低浓度时促进TNFα的生成，在高浓度时抑制其生成；通过EP4主要下调了VEGF的生成，同时上调IL-1β以及TNFα的生成。PGE2对趋化因子MCP-1并未见明显的调节作用。
4. PGF2α以及PGE2均参与分娩前期炎症相关因子的生成，一方面通过促进促炎因子的生成创造了分娩启动前期子宫局部炎症微环境的建立，同时刺激子宫平滑肌分泌的趋化因子对于白细胞向宫内的招募富集，进一步扩大炎症反应的进行提供了有利条件。
二、PGs通过不同受体对妊娠子宫平滑肌细胞上子宫收缩相关蛋白表达的调节作用
1.前列腺素F2α通过激活Gq蛋白，经胞内一系列信号分子P38,PI3K和PLC-β-PKC等的传递，介导了对子宫收缩相关蛋白CX43，PTGS-2以及OTR表达的上调作用，而同时以负反馈调节的方式降低了自身受体的表达。
2. PGE2则分别通过收缩性受体EP1/3上调了CX43，PTGS-2，OTR以及PTGFR的表达，而舒张性受体EP2则通过抑制OTR以及PTGFR的表达降低子宫平滑肌对催产素和前列腺素等宫缩剂的敏感性。通过两类受体亚型的相互协调作用，完成对收缩相关蛋白的表达的精细调节。
三、PGs通过不同受体对妊娠子宫平滑肌细胞上转录因子ZEBs的调节作用
1. PGF2α可剂量依赖性减少ZEB两种亚型蛋白水平的表达。
2．PGE2主要是发挥着下调ZEB1的调节作用，但是其通过EP1/3可上调ZEB1和ZEB2；通过EP2和EP4下调ZEB1以及ZEB2的蛋白表达。
结论：
本研究表明，临近分娩时孕妇羊水中高表达的前列腺素PGF2α及PGE2在子宫肌局部通过自分泌或旁分泌的方式，一方面可通过促进炎症相关的促炎因子及子的表达，参与构建宫内局部炎症微环境，同时也通过上调VEGF的表达改变子宫肌细胞的通透性，刺激宫内趋化因子的表达，从而为炎症反应的扩大提供有利条件。另一方面，通过上调子宫收缩相关蛋白的表达来直接激活子宫肌的收缩状态，为分娩的顺利进行做好准备。
Numerous physiological processes, like implantation, pregnancy maintaince and thetrigger of parturtiton, have close relationship with maternal immune system. Evidenceindicated that the establishment of inflammatory environment in intrauterine organscontributes to the initiation of parturition. The cytokines and chemokines activate themyometrium contractile ability changes via modulating contraction-related fators, andfurther more initate the parturition of labor. However there is no definite conclusion aboutthe regulation mechanism of inflammation factors during pregnancy and parturition.Considering as the most powerful contractile agonist of myometrium, PGs was reported todelay the stimulatory effect in clinical application as the drug induced labor. Thus thisfinding indicated that the regulatory mechanism of PGs on myometrium contractility mightgo through the uterus activation process in the early stage of parturition initiation and latersitmulates the regular contration in uterus. Reports demonstrated that the level of PGsdetected in amion fluid before parturition arised significantly which possibly contribute tothe uterine activation process during the early parturition. Without clarified explainationabout the hypothesis, we studied whether PGF2α and PGE2modulate the inflammation-related factors expression during normal pregnancy based on the cultured myometrialsmooth muscle cells.
The contractility of uterus is influenced by changes of hormones level, expression ofcontractile proteins and other factors. The alteration of contractile protein family onexpression and function represents the contract ability of uterus. PGs have been discoveredinvolved in the regulation of some contractile proteins. However more studies are requiredfor the possible activated signal pathway mechanism triggered by PGF2α and PGE2inmyometrial cells. Here in our study, PTGS-2, CX43, OTR and PTGFR are taken as fourproxies for the uterine activation protein family (UAPs).
In the third part, the role of transcriptional factor，Zinc E box binding homeobox,(ZEB) was taken into consideration that particicpated in the effect of PGs on uterineactivation process. Evidences indicated that ZEBs could directly bind to the promoters ofOTR and CX43and futher regulated their protein abundance. Therefore, we focused onwhether ZEBs medicatd partially the regulation of PGs on uterine activation proteinsexpression. Main results:
1. Regulation of inflammatory cytokines expression mediated by prostaglandinsvia different receptors
1) In the uterine activation process, PGF2α stimulated the outputs of pro-inflammatory cytokines, such as IL-6, IL-1β, the outputs of chemokines, like IL-8, MCP-1,and growth factor VEGF output, while decreased the output of cytokine TNFα.
2) PGF2α receptor, PTGFR, trigger the intracellular multiple signal pathways toregulate the outputs of cytokines and chemokines. The outputs of IL-6，IL-1β, IL-8,MCP-1，VEGF and TNFα were modulated by PLC-β-PKC pathway. While the activationof Calcineurin-NFAT pathway involved in the regulation on MCP-1and TNFα outputs.The output of MCP-1was also mediated by P38-STATs pathway, while the PI3K activationparticipated in the regulation of MCP-1and VEGF outputs.
3) PGE2via EP1/3up-regulated the outputs of IL-6, VEGF, TNFα, while decreasedIL-1β output. EP2agonist stimulated the outputs of IL-6, IL-8, IL-1β, and VEGF dose-dependently. But there exist the dual effect of EP2mediating the output of TNFα, i.e itshowed the stimulatory effect at the low concentration while decreased TNFα output at thehigh concenctration. And EP4agonist mainly down-regulated VEGF output and increasedIL-1β and TNFα outputs. Compared withhere is no significant effect on chemokine MCP-1output by PGE2.
2. Regulation of uterine activation proteins expression mediated byprostaglandins via different receptors
1) PGF2α via its Gq protein-coupled receptor PTGFR, activated intracellular PLCβ-PKC pathway and other signal factors to up-regulate the expression of uterine activationproteins, such as CX43, PTGS-2, OTR. Meanwhile PGF2α showed the negative feedbackmodulation on its own receptor expression.
2) The contractile receptors EP1/3of PGE2mediated the stimulatory effect on UAPsexpression. While the relaxant receptor EP2and EP4mainly reduced the sensitivity ofmyometrial cells on oxytocin and PGs by down-regulating their receptor expression.Therefore PGE2achieved the subtle regulation on the uterine activation proteinsabundance by the balanced coordination among receptors.
3. Regulation of transcript factor--ZEBs expression mediated by prostaglandinsvia different receptors
1) PGF2α downregulated ZEB1and ZEB2protein abundances in pregnant myomtrial cells.
2) PGE2mainly decreased ZEB1expression while ZEB2abundance remained at thesimilar level. However the contractile receptor EP1/3specific agonist increased ZEBsexpression while EP2and EP4agonists downregulated their abundances.Conclusion
In concluation, our study demonstrated that the arising level of PGF2α and PGE2inamnion fluid of pregnant women, took act on myometrium via autocrine or paracrine mean.On one hand, PGs contributed the micro inflammatory environment in intrauterine organsby promoting inflammation-related cytokines and chemokines expression. Meanwhile theupregulated VEGF level may contribute to the permeability of myometrial cells allowingmigration of leukocytes to uterus. On the other hand, the up-regulation of uterus contractileproteins can activate myometrium and prepare for the parturition.
引文
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