IL-18、iNOS和NF-κB在妊娠和流产大鼠中的表达及意义
摘要
成功的胚胎植入以及随后的妊娠维持过程均要求细胞因子、激素和免疫因子在机体内正确分布和表达,一旦这些物质在时间和空间上的表达紊乱就会引发各种妊娠疾病,甚至造成流产。然而调控这一过程的许多生物化学信息分子表达的空间及时间特性还未完全阐明。近些年的研究发现,白细胞介素-18(Interleukin-18, IL-18)、诱导型一氧化氮合酶(Inducible nitric oxide synthase , iNOS)和核转录因子(Nuclear factor-kappa B,NF-κB)与生殖密切相关,但IL-18、iNOS和NF-κB在妊娠和流产中的作用及关系还不清楚。IL-18和iNOS可作为神经-免疫-内分泌的调节因子,因此,本试验采用超敏感的免疫组织化学SP法和图像分析法对非妊娠(发情期)、妊娠各期(胚胎植入前期、植入期、植入后期、妊娠中期和妊娠晚期)和早期流产大鼠下丘脑-垂体-性腺轴中IL-18和iNOS的分布及表达特点进行了研究,采用RT-PCR方法检测了非妊娠、正常妊娠早期及早期流产大鼠子宫中IL-18和iNOS mRNA的水平,用ELISA和硝酸酶还原法检测了外周血中IL-18和NO水平的变化。由于NF-κB是一种信号转导因子,主要在局部发挥作用,故本实验采用免疫组织化学SP法和图像分析法对非妊娠、妊娠各期和早期流产大鼠卵巢和子宫中NF-κB的分布及表达特点和激活程度进行了研究。主要结果如下: 1. IL-18和iNOS在非妊娠和妊娠各期大鼠下丘脑视前交叉上核、视上核、室旁核等24个核团均有表达,分布广泛;在腺垂体、垂体中间部和神经垂体纤维中也有分布;卵巢黄体颗粒细胞、卵泡颗粒细胞、卵泡膜细胞、卵母细胞、卵泡液、血管内皮细胞、间质腺、生殖上皮及基质中均存在;子宫腔上皮细胞、腺上皮细胞、基质细胞、子宫平滑肌细胞、血管内皮细胞及平滑肌细胞中也有表达。提示IL-18和iNOS可能以自分泌或旁分泌的方式参与下丘脑、垂体、卵巢及子宫功能的调节。
2. IL-18和iNOS在下丘脑、垂体、卵巢及子宫中的表达量在妊娠的不同时期有所差异:在妊娠早期表达较多(除妊娠初期下丘脑IL-18水平较低),中期明显降低,而晚期又有所回升。提示IL-18和iNOS参与整个妊娠过程,并且在妊娠过程中的表达程度受到严格的时间和空间调控。从时间上看,IL-18和iNOS在胚胎植入前后和妊娠晚期表达较多,提示IL-18和iNOS在胚胎植入过程和分娩启动中发挥重要作用。从空间上看,IL-18和iNOS在下丘脑和垂体水平参与了对妊娠的调节,通过下丘脑-垂体-卵巢轴调控子宫母胎界面的微环境。妊娠过程中卵巢和子宫IL-18及iNOS的规律性表达表明,IL-18和iNOS可调节妊娠期卵泡和黄体功能,进而影响卵巢类固醇的生成;同时也参与了母体胎儿界面免疫耐受的调节。机体各部位的共同协作为胎儿的发育提供了有利的免疫微环境。
3.在妊娠过程中大鼠下丘脑IL-18和iNOS水平的变化主要在视前区、视上区和漏斗部的弓状核,提示下丘脑的这些部位与生殖密切相关。而前连合核等个别核团表达状况特殊,提示他们可能还有其他生理功能。
4. NF-κBp65在非妊娠和妊娠各期大鼠卵巢和子宫中均有表达,并呈规律性变化:在妊娠早期表达较多,中期明显降低,而晚期又有所回升,提示NF-κBp65参与妊娠过程中卵巢及子宫功能的调节,在胚胎植入和分娩启动中发挥重要作用。在整个妊娠过程中95%的NF-κBp65位于细胞质中,仅有5%位于细胞核,提示NF-κBp65活性处于抑制状态,有利于妊娠的维持。
5.在妊娠早期孕鼠胎盘锥、妊娠中期和晚期胎盘中均有IL-18、iNOS和NF-κBp65表达,提示IL-18、iNOS和NF-κBp65可作为母体与胎儿间的信息传递因子,在胎盘和胎儿的发育过程中发挥重要作用。
6.流产组大鼠外周血中IL-18和NO的水平明显低于同期正常妊娠组,下丘脑-垂体-性腺轴中表达的IL-18和iNOS也较正常妊娠和非妊娠组大鼠明显降低,提示下丘脑-垂体-卵巢IL-18和iNOS表达的减少可能是流产发生的原因之一。推测下丘脑-垂体-性腺轴中IL-18和iNOS表达减少,使得其对下丘脑、垂体和卵巢的内分泌功能的调节不足,各种激素和因子表达紊乱,最终使母胎界面的免疫微环境失衡,母体对胎儿产生排斥,诱发流产。
7.流产时,大鼠下丘脑表达iNOS的小胶质细胞增多,而小胶质细胞的激活与炎症的发生密切相关,提示iNOS可能与小胶质细胞的激活有关,并在流产的炎症过程中发挥重要作用。
8.与正常妊娠和非妊娠组大鼠相比,流产大鼠卵巢NF-κBp65的表达明显减少。NF-κBp65是凋亡抑制因子,推测NF-κBp65表达减少,不足以抑制凋亡基因的表达,导致卵泡和黄体颗粒细胞凋亡,卵泡闭锁,黄体溶解,诱发流产;流产大鼠子宫中NF-κBp65的表达明显增加,且32%NF-κBp65阳性产物位于细胞核内(正常妊娠仅为5%),提示子宫NF-κBp65的表达增加和过度激活可能是流产发生的原因之一。
9.在妊娠和流产过程中大鼠下丘脑和垂体IL-18与iNOS水平的变化趋势基本一致,相关性分析表明二者呈正相关,提示二者在妊娠和流产过程中对下丘脑及垂体功能的调节具有协同作用。而卵巢中IL-18、iNOS和NF-кB的水平在妊娠和流产过程中变化趋势也一致,呈正相关,提示三者在妊娠和流产过程中对卵巢功能调节有协同作用。然而这三种活性物质在妊娠和流产过程中对子宫功能的调节存在差异:在妊娠过程中三者呈正相关,而在流产过程中IL-18与NF-кB呈正相关,iNOS与NF-кB呈负相关。综合这些物质在流产中的变化,推测在流产过程中NF-κB通过促进子宫肌IL-18 mRNA及蛋白的表达,抑制子宫内膜IL-18及子宫iNOS mRNA及蛋白的表达,使子宫的免疫调控失衡,诱发流产。
Proper distribution and expression of cytokine, hormone and immune factor in organism is a prerequisite for successful implantation and subsequent pregnancy maintenance. If these factors distribute and express disorderly, pregnancy disease and abortion will initiate. But biochemical signals that control such events have not been well characterized. Recent research shows IL-18, iNOS and NF-кB hav close relation with reproduction. But their relation with pregnancy and abortion is unclear. IL-18 and iNOS may act as regulator factors among nerve, immunity and endocrine, so we studied the distribution and expression of IL-18 and iNOS in rat hypothalamus-pituitary gland-gonad axis during oestrus, all pregnancy period and early abortion by immunohistochemistry SP method, the expression of IL-18 and iNOS mRNA in rat uterus of oestrus, pregnancy 9 days and abortion in pregnancy 9 days by RT-PCR method, the level of IL-18 and NO in rat serum of oestrus, pregnancy 9 days and abortion in pregnancy 9 days. NF-κB may act as a signal transduction factor, so we studied the distribution and expression of NF-κB in rat ovary and uterus during oestrus, all pregnancy period and early abortion by immunohistochemistry SP method and oboserved the activation degree of NF-κB in all groups. The main result as follow:
1. IL-18 and iNOS extensively distributed in 24 hypothalami nucleus of oestrus and pregnancy rat, such as pre-opticus suprachiasmatic nucleus, supraoptic nucleus, paraventricular nucleus. In rat pituitary, IL-18 and iNOS immunoactivity product were found in adenohypophysis cell, pituitary pars intermedia cell and neurohypophysis fiber; In rat ovary, IL-18 and iNOS mainly existed in ovarian follicular granular cell and theca cell, oocyte, follicular fluid, corepus luteam granular cell, vascular endothelial cell, interstitial gland, germinal epithelium and matrix. In rat uterus, IL-18 and iNOS mainly prensented in endometrial or decidual luminal epithelium, glandular epithelium, stroma or decidual cells, myometrium, vascular endothelial cell and vascular smooth muscle cell. The result shows IL-18 and iNOS may regulate the function of hypothalamus, pituitary gland, ovary and uterus in autocrine and paracrine ways.
2. The expression of IL-18 and iNOS in rat hypothalamus-pituitary gland-gonad axis was different in different prgnancy period. The level of IL-18 and iNOS was higher in early pregnancy, lower in mid trimester of pregnancy and higher in late trimester of pregnancy. The result shows IL-18 and iNOS participate all pregnancy and their expression was controled strictly in time and space modes. In time mode, the level of IL-18 and iNOS was high in circa of embryo implantation and late trimester of pregnancy. It shows IL-18 and iNOS may have great roles in the process of embryo implantation and parturition. In space mode, IL-18 and iNOS in hypothalamus and pituitary may participate the regulation of all pregnancy process. They may control the function hypothalamus-pituitary gland-gonad axis to affect the microenveronment of mother-foetus interface. The expression of IL-18 and iNOS in ovary and uterus may regulate the function of ovarian follicle and corepus luteum, affect the production of ovary steroid and the immunotolerance in mother-foetus interface. These can protect foetus from the mother rejection and provide a good enviroment for foetus development.
3. The level change of IL-18 and iNOS in hypothalamus mainly presented in preoptica area, supraoptic region and arcuate nucleus in fimbria. So it hints these hypothalamic parts may have close relation with reproduction. However, the level change tendency of IL-18 and iNOS in some nucleus, such as commissural nucleus, was unusual.It shows they may have other physiologic fuction.
4. NF-κBp65 existed in rat ovary and uterus during oestrus and all pregnancy period. And the level NF-κBp65 presented a regulated change: higher in early pregnany, lower in mid trimester of pregnancy and increased in late trimester of pregnancy. The result shows NF-κBp65 may as a important regulator of the function of ovary and uterus and have great roles in the process of embryo implantation and parturition. NF-κBp65 in cytoplasm has incompentence.when it enters into nucleus, it has a activity. All pregnancy process, 95% NF-κBp65 main exist in cytoplasm and 5% in nucleus. The result shows NF-κBp65 in inhibition activity may promote the pregancy maintence.
5. The expression of IL-18, iNOS and NF-κBp65 was found in rat ectoplacental cone in early pregnancy and placenta in mid trimester of pregnancy and late trimester of pregnancy. The result shows IL-18, iNOS and NF-κBp65 may act as information transfer factors between mother and foetus and play a great role in development placenta and foetus.
6. Compare to the same norm pregnacy group, the level of IL-18 and NO in abortion rat serum and the expression of IL-18 and iNOS in abortion rat hypothalamus-pituitary gland-gonad axis were obviously decreased. The result shows the expression of IL-18 and iNOS in rat maybe a factor for inducing abortion. The decreased expression of IL-18 and iNOS in rat hypothalamus-pituitary gland-gonad axis may induce the regulation of IL-18 and iNOS on the endocrine function of hypothalamus- pituitary gland-gonad axis disorder, which could induced hormone and cytokine secreted disorderly and affected the microenveronment of mother-foetus interface. Finally, the balance of immunotolerance in mother-foetus interface was breaked, the rejection between mother and foetus increased, and abortion was induced.
7. when rat aborted, the number of microglia which contain iNOS immunoactive product increased. Because of the activity of microglia have a close relation with inflammation development. So the result shows iNOS may activates microglia and play a important role in inflammation development during abortion process.
8. Compare to the same norm pregnacy group and oestrus group, the expression of NF-κB p65 in abortion rat ovary was obviously decreased . NF-κBp65 is a anti-apoptosis factor. So we suppose the decreased expression of NF-κBp65 will not inhibit the expression of apoptosis gene and induce the ovarian follicular and corepus luteum granular cell apoptosis. Sequentia follicular atresia and luteolysis, the abortion is induced. However, the expression of NF-κBp65 in abortion rat uterus was notably increased and the cell number of NF-κBp65 in nucleus ( 32% compared with 5%)significantly increased. All results show the increased expression of NF-κBp65 and NF-κBp65 activity in rat uterus may as a factor for abortion genesis .
9. In pregnancy and abortion process, the change tendency of IL-18 and iNOS in rat hypothalamus and pituitary gland is basic coincidence. By correlation analysis, it has positive correlation between IL-18 and iNOS. The result shows it has synergism between IL-18 and iNOS in regulating the function of hypothalamus and pituitary gland.In rat ovary, the change tendency of IL-18 , iNOS and NF-κBp65 in pregnancy and abortion process is basic coincidence too. The result shows their have synergism in regulating the function of ovary. However, in rat uterus the change tendency of IL-18, iNOS and NF-κBp65 in pregnancy process is different from that in abortion process. In pregnancy process, these factors have a positive correlation. It shows their have synergism in regulating the function of pregnancy uterus. In abortion process, it has a positive correlation between IL-18 and NF-κBp65, a negative between NF-κBp65 and iNOS. The result shows it has a synergism between IL-18 and NF-κBp65, antogonism between NF-κB p65 and iNOS, in regulating the function of uterus during abortion. Combined with the change of these substance in abortion process, it suppose NF-κBp65 is not only prompte the expression of IL-18 mRNA and protein in myometrium but also inhibit that in endometrial and the expression of iNOS mRNA and protein in uterus.
2. IL-18和iNOS在下丘脑、垂体、卵巢及子宫中的表达量在妊娠的不同时期有所差异:在妊娠早期表达较多(除妊娠初期下丘脑IL-18水平较低),中期明显降低,而晚期又有所回升。提示IL-18和iNOS参与整个妊娠过程,并且在妊娠过程中的表达程度受到严格的时间和空间调控。从时间上看,IL-18和iNOS在胚胎植入前后和妊娠晚期表达较多,提示IL-18和iNOS在胚胎植入过程和分娩启动中发挥重要作用。从空间上看,IL-18和iNOS在下丘脑和垂体水平参与了对妊娠的调节,通过下丘脑-垂体-卵巢轴调控子宫母胎界面的微环境。妊娠过程中卵巢和子宫IL-18及iNOS的规律性表达表明,IL-18和iNOS可调节妊娠期卵泡和黄体功能,进而影响卵巢类固醇的生成;同时也参与了母体胎儿界面免疫耐受的调节。机体各部位的共同协作为胎儿的发育提供了有利的免疫微环境。
3.在妊娠过程中大鼠下丘脑IL-18和iNOS水平的变化主要在视前区、视上区和漏斗部的弓状核,提示下丘脑的这些部位与生殖密切相关。而前连合核等个别核团表达状况特殊,提示他们可能还有其他生理功能。
4. NF-κBp65在非妊娠和妊娠各期大鼠卵巢和子宫中均有表达,并呈规律性变化:在妊娠早期表达较多,中期明显降低,而晚期又有所回升,提示NF-κBp65参与妊娠过程中卵巢及子宫功能的调节,在胚胎植入和分娩启动中发挥重要作用。在整个妊娠过程中95%的NF-κBp65位于细胞质中,仅有5%位于细胞核,提示NF-κBp65活性处于抑制状态,有利于妊娠的维持。
5.在妊娠早期孕鼠胎盘锥、妊娠中期和晚期胎盘中均有IL-18、iNOS和NF-κBp65表达,提示IL-18、iNOS和NF-κBp65可作为母体与胎儿间的信息传递因子,在胎盘和胎儿的发育过程中发挥重要作用。
6.流产组大鼠外周血中IL-18和NO的水平明显低于同期正常妊娠组,下丘脑-垂体-性腺轴中表达的IL-18和iNOS也较正常妊娠和非妊娠组大鼠明显降低,提示下丘脑-垂体-卵巢IL-18和iNOS表达的减少可能是流产发生的原因之一。推测下丘脑-垂体-性腺轴中IL-18和iNOS表达减少,使得其对下丘脑、垂体和卵巢的内分泌功能的调节不足,各种激素和因子表达紊乱,最终使母胎界面的免疫微环境失衡,母体对胎儿产生排斥,诱发流产。
7.流产时,大鼠下丘脑表达iNOS的小胶质细胞增多,而小胶质细胞的激活与炎症的发生密切相关,提示iNOS可能与小胶质细胞的激活有关,并在流产的炎症过程中发挥重要作用。
8.与正常妊娠和非妊娠组大鼠相比,流产大鼠卵巢NF-κBp65的表达明显减少。NF-κBp65是凋亡抑制因子,推测NF-κBp65表达减少,不足以抑制凋亡基因的表达,导致卵泡和黄体颗粒细胞凋亡,卵泡闭锁,黄体溶解,诱发流产;流产大鼠子宫中NF-κBp65的表达明显增加,且32%NF-κBp65阳性产物位于细胞核内(正常妊娠仅为5%),提示子宫NF-κBp65的表达增加和过度激活可能是流产发生的原因之一。
9.在妊娠和流产过程中大鼠下丘脑和垂体IL-18与iNOS水平的变化趋势基本一致,相关性分析表明二者呈正相关,提示二者在妊娠和流产过程中对下丘脑及垂体功能的调节具有协同作用。而卵巢中IL-18、iNOS和NF-кB的水平在妊娠和流产过程中变化趋势也一致,呈正相关,提示三者在妊娠和流产过程中对卵巢功能调节有协同作用。然而这三种活性物质在妊娠和流产过程中对子宫功能的调节存在差异:在妊娠过程中三者呈正相关,而在流产过程中IL-18与NF-кB呈正相关,iNOS与NF-кB呈负相关。综合这些物质在流产中的变化,推测在流产过程中NF-κB通过促进子宫肌IL-18 mRNA及蛋白的表达,抑制子宫内膜IL-18及子宫iNOS mRNA及蛋白的表达,使子宫的免疫调控失衡,诱发流产。
Proper distribution and expression of cytokine, hormone and immune factor in organism is a prerequisite for successful implantation and subsequent pregnancy maintenance. If these factors distribute and express disorderly, pregnancy disease and abortion will initiate. But biochemical signals that control such events have not been well characterized. Recent research shows IL-18, iNOS and NF-кB hav close relation with reproduction. But their relation with pregnancy and abortion is unclear. IL-18 and iNOS may act as regulator factors among nerve, immunity and endocrine, so we studied the distribution and expression of IL-18 and iNOS in rat hypothalamus-pituitary gland-gonad axis during oestrus, all pregnancy period and early abortion by immunohistochemistry SP method, the expression of IL-18 and iNOS mRNA in rat uterus of oestrus, pregnancy 9 days and abortion in pregnancy 9 days by RT-PCR method, the level of IL-18 and NO in rat serum of oestrus, pregnancy 9 days and abortion in pregnancy 9 days. NF-κB may act as a signal transduction factor, so we studied the distribution and expression of NF-κB in rat ovary and uterus during oestrus, all pregnancy period and early abortion by immunohistochemistry SP method and oboserved the activation degree of NF-κB in all groups. The main result as follow:
1. IL-18 and iNOS extensively distributed in 24 hypothalami nucleus of oestrus and pregnancy rat, such as pre-opticus suprachiasmatic nucleus, supraoptic nucleus, paraventricular nucleus. In rat pituitary, IL-18 and iNOS immunoactivity product were found in adenohypophysis cell, pituitary pars intermedia cell and neurohypophysis fiber; In rat ovary, IL-18 and iNOS mainly existed in ovarian follicular granular cell and theca cell, oocyte, follicular fluid, corepus luteam granular cell, vascular endothelial cell, interstitial gland, germinal epithelium and matrix. In rat uterus, IL-18 and iNOS mainly prensented in endometrial or decidual luminal epithelium, glandular epithelium, stroma or decidual cells, myometrium, vascular endothelial cell and vascular smooth muscle cell. The result shows IL-18 and iNOS may regulate the function of hypothalamus, pituitary gland, ovary and uterus in autocrine and paracrine ways.
2. The expression of IL-18 and iNOS in rat hypothalamus-pituitary gland-gonad axis was different in different prgnancy period. The level of IL-18 and iNOS was higher in early pregnancy, lower in mid trimester of pregnancy and higher in late trimester of pregnancy. The result shows IL-18 and iNOS participate all pregnancy and their expression was controled strictly in time and space modes. In time mode, the level of IL-18 and iNOS was high in circa of embryo implantation and late trimester of pregnancy. It shows IL-18 and iNOS may have great roles in the process of embryo implantation and parturition. In space mode, IL-18 and iNOS in hypothalamus and pituitary may participate the regulation of all pregnancy process. They may control the function hypothalamus-pituitary gland-gonad axis to affect the microenveronment of mother-foetus interface. The expression of IL-18 and iNOS in ovary and uterus may regulate the function of ovarian follicle and corepus luteum, affect the production of ovary steroid and the immunotolerance in mother-foetus interface. These can protect foetus from the mother rejection and provide a good enviroment for foetus development.
3. The level change of IL-18 and iNOS in hypothalamus mainly presented in preoptica area, supraoptic region and arcuate nucleus in fimbria. So it hints these hypothalamic parts may have close relation with reproduction. However, the level change tendency of IL-18 and iNOS in some nucleus, such as commissural nucleus, was unusual.It shows they may have other physiologic fuction.
4. NF-κBp65 existed in rat ovary and uterus during oestrus and all pregnancy period. And the level NF-κBp65 presented a regulated change: higher in early pregnany, lower in mid trimester of pregnancy and increased in late trimester of pregnancy. The result shows NF-κBp65 may as a important regulator of the function of ovary and uterus and have great roles in the process of embryo implantation and parturition. NF-κBp65 in cytoplasm has incompentence.when it enters into nucleus, it has a activity. All pregnancy process, 95% NF-κBp65 main exist in cytoplasm and 5% in nucleus. The result shows NF-κBp65 in inhibition activity may promote the pregancy maintence.
5. The expression of IL-18, iNOS and NF-κBp65 was found in rat ectoplacental cone in early pregnancy and placenta in mid trimester of pregnancy and late trimester of pregnancy. The result shows IL-18, iNOS and NF-κBp65 may act as information transfer factors between mother and foetus and play a great role in development placenta and foetus.
6. Compare to the same norm pregnacy group, the level of IL-18 and NO in abortion rat serum and the expression of IL-18 and iNOS in abortion rat hypothalamus-pituitary gland-gonad axis were obviously decreased. The result shows the expression of IL-18 and iNOS in rat maybe a factor for inducing abortion. The decreased expression of IL-18 and iNOS in rat hypothalamus-pituitary gland-gonad axis may induce the regulation of IL-18 and iNOS on the endocrine function of hypothalamus- pituitary gland-gonad axis disorder, which could induced hormone and cytokine secreted disorderly and affected the microenveronment of mother-foetus interface. Finally, the balance of immunotolerance in mother-foetus interface was breaked, the rejection between mother and foetus increased, and abortion was induced.
7. when rat aborted, the number of microglia which contain iNOS immunoactive product increased. Because of the activity of microglia have a close relation with inflammation development. So the result shows iNOS may activates microglia and play a important role in inflammation development during abortion process.
8. Compare to the same norm pregnacy group and oestrus group, the expression of NF-κB p65 in abortion rat ovary was obviously decreased . NF-κBp65 is a anti-apoptosis factor. So we suppose the decreased expression of NF-κBp65 will not inhibit the expression of apoptosis gene and induce the ovarian follicular and corepus luteum granular cell apoptosis. Sequentia follicular atresia and luteolysis, the abortion is induced. However, the expression of NF-κBp65 in abortion rat uterus was notably increased and the cell number of NF-κBp65 in nucleus ( 32% compared with 5%)significantly increased. All results show the increased expression of NF-κBp65 and NF-κBp65 activity in rat uterus may as a factor for abortion genesis .
9. In pregnancy and abortion process, the change tendency of IL-18 and iNOS in rat hypothalamus and pituitary gland is basic coincidence. By correlation analysis, it has positive correlation between IL-18 and iNOS. The result shows it has synergism between IL-18 and iNOS in regulating the function of hypothalamus and pituitary gland.In rat ovary, the change tendency of IL-18 , iNOS and NF-κBp65 in pregnancy and abortion process is basic coincidence too. The result shows their have synergism in regulating the function of ovary. However, in rat uterus the change tendency of IL-18, iNOS and NF-κBp65 in pregnancy process is different from that in abortion process. In pregnancy process, these factors have a positive correlation. It shows their have synergism in regulating the function of pregnancy uterus. In abortion process, it has a positive correlation between IL-18 and NF-κBp65, a negative between NF-κBp65 and iNOS. The result shows it has a synergism between IL-18 and NF-κBp65, antogonism between NF-κB p65 and iNOS, in regulating the function of uterus during abortion. Combined with the change of these substance in abortion process, it suppose NF-κBp65 is not only prompte the expression of IL-18 mRNA and protein in myometrium but also inhibit that in endometrial and the expression of iNOS mRNA and protein in uterus.
引文
[1] 陈竹钦,胡冬梅. 蜕膜细胞因子网络平衡状态与流产[J].中国实用妇科与产科杂志, 1999,15 (3): 145.
[2] 胡冬梅,陈竹钦,曹咏清.蜕膜细胞成分及其免疫生物学特性的研究进展[J].生殖与避孕,1998,18(3):131-135.
[3] 胡冬梅,陈竹钦,颜建华,等.正常早孕蜕膜非免疫细胞免疫活性的实验研究[J].中华妇产科杂志,1999,34(9):533-535.
[4] Olivares EG, Montes MJ, Oliver C, et a1.Cultured human decidual stromal cells express B7-1(CDS0) and B7-2(CD86)and stimulate al!ogeneic T cells[J].Biol Reprod,1997,57: 609- 615.
[5] Imaik K, Maeda M, Fujiwara H, et al.Human endometrial stromal cells and decidual cell express cluster of differentiation (CD)13 antigen/amninopeptidase N and CD10 antigen/neutral endopeptidase[J].Biol Reprod,1992,46:328-334.
[6] Raghupathy R. Th1-type immunity is incompatible with successful pregnancy [J]. Immunol Today, 1997,18 (10):478-482
[7] Wilczynski JR, Tchorzewski H, Banasik M, et al. Lymphocyte subset distribution and cytokine secretion in third trimester decidua in normal pregnancy and preeclampsia[J]. Eur J Obstet Gynecol Reprod Biol, 2003, 109(1):8-15.
[8] Hossein H, Mahroo M, Abbas A, et al. Cytokine production by peripheral blood mononuclear cells in recurrent miscarriage[J]. Cytokine, 2004,28(2):83-86.
[9] Daher S, de-Arruda-Geraldes-Denardi K, Blotta MH, et al. Cytokines in recurrent pregnancy loss[J]. J Reprod Immunol, 2004, 62 (1-2): 151-157.
[10] Somi S S.Cytokines during early pregnancy mammals[J].Anim Reprod sci,2003,75:73-94.
[11] Piccinni MP, Scaletti C, Vultaggio A, et a1. Defective production of ILF,M-CSF and Th2-type cytokines by T ceils at fetomaternal interface is associated with pregnancy loss[J].J Reprod Immunol, 2001, 52:35- 43.
[12] Hunt JS, Petroff MG, Burneff TG.Uterine leukocytes:key player in pregnancy[J].Cell and Develop Biol, 2000,11:127-137.
[13] Somi SS.Cytokines during early pregnancy mammals [J].Anim Reprod sci,2003,75:73-94.
[14] Uckan D, Steele A, Cherry B, et al. Trophoblasts expression Fas ligand : A proposed mechanism for immune privilege in placenta and maternal invasion[J] . Mol Hum Reprod, 1997,3 (8) :655 – 662.
[15] Hammer A, Dohr G. Expression of Fas-ligand in first trimester and term human placental villi [J] . J Reprod Immunol, 2000, 46 (2) : 83 -90.
[16] Eis A, Myatt L, Brockman DE, et al. Inducible (type Ⅱ) nitric oxide synthase in human placental villous tissue of normotensive pre-ellamptic and intranterine growth-restricted pregnancies[J] . AmJ Reprod Immunol, 1997, 38 (4) :289-294.
[17] Clark DA , Keil A ,Chen Z ,et al. Placental trophoblast from successful human pregnancies expresses the tolerance signaling molecule , CD200 (OX-2) [J] . Am J Reprod Immunol , 2003,50 (3) :187–195.
[18] Veen RC, Roberts LJ. Nitric Oxide Synthase Expression and NitricOxide [J] .Toxicity in Oligodendro- cytes Cell Immunol, 1999, 193 (2) :194-201.
[19] Odamura H, Tsutsi H, Komatsu T, et al. Cloning of a new cytokine that induces IFN-gamma Production by T cell[J].Nature,1995,378(6552):88-91 .
[20] Nakamura K, Okamura H, Nagata K, et al. Purification of a factor which provides a costimulatory signal for gamma interferon production[J].Infect Immunol,1993,61 (1): 64.
[21] Okamura H, Nagata K, Komatsu H, et al. A novel costimulatory factor for gamma interferon induction found in the livers of minusc ausese ndotoxic shock[J]. Infect Immune,1995,63 (10):3966.
[22] Ushio S, Namba M,Okura T, et al. Cloning of the cDNA for human IFN gamma-inducing factor, Expressionin Escherichia coli, and studies on the biologic actifities of the protein[J].J Immunol,1996,156(11):4274-4279.
[23] Kawakami K.Interleukin-18 and host defense against infectious pathogens[J].J Immunother, 2002,25 (suppl 1):512-519.
[24] Park H,Kim JE,Lee JY,et al.Increased expression of IL-18 in cutaneous graft- versus-host disease[J]. Immunol Lett,2004,95(1):57-61.
[25] Kaiser P. Turkey and chicken interleukin 18 (IL-18) share high se quence identity, but have different polyadenylation sites in their 3′UTR [J]. Dev Comp Immunol, 2002; 26 (8):681-687.
[26] Burns K, Martinon F, Esslinger C, et al. MyD88, an adapter protein involved in interleukin-1 signaling [J]. J Biol Chem, 1998, 273 (20) : 12203-12209.
[27]Andre R, Wheeler RD, Collins PD, et al. Identification of a truncated IL-18R beta mRNA: a putative regulator of IL-18 expressed in rat brain[J]. J N euroimm unol, 2003, 145 (122):40-45.
[28] Kohno K, Kataoka J, Ohtsuki T, et al. IFN-γ-inducing factor ( IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12 [J]. J Immunol, 1997, 158: 1541-1550.
[29] Micallef MJ, Ohtauki T, Kohno K, et al. Interferon-γ inducing factor enhances T helper 1 cytokine production by stimulated human T cell: synergism with interleukin-12 for interferon-γ production[J]. Eur J Immunol, 1996, 26: 1647-1651.
[30] Naumnik W, Chyczewska E, Kovalchuk O, et al. Serum levels of interleukin-18 ( IL-18) and soluble interleukin-2 receptor ( sIL-2R) in lung cancer[J]. Rocz Akad Med Bialymst, 2004, 49: 246 -251.
[31] Hata H, Yoshimoto T, Hayashi N, et al.IL-18 togather with anti-CD3 antibody induces humans Th1 cells to produce Th1- and Th2-cytokines and IL-8[J].Int Immunol,2004,16 (2):1733- 1739.
[32] Takeda K, Tsutsui H, Yoshimoto T, et al. Defective NK cell activity and Th1 response in IL-18- deficient mice [J]. Immunity, 1998, 8: 383 - 390. [33 ] Okano F, Yamada K. Canine interleukin-18 induced apop tosis and enhances Fas ligand mRNA exp- ression in a canine carcinoma cell line[J]. Anticancer Res, 2000, 20: 3411-3416.
[34] Tomura M, Zhou XY, Maruo S, et al. A critical role for IL-18 in the proliferation and activation of NK1,1+CD3 cells. J Immunol,1998,160(10):4738- 4736.
[35] Shin HD, Kim LH, Park BL, et al. Association of interleukin 18 (IL18) polymorphisms with specific IgE levels to mite allergens among asthmatic patients[J]. Allergy,2005,60(7):900-906.
[36] Jin M, Jung HJ, Choi JJ, et al. Activation of seclective transcription factors and cytokines by water-souble extract from lentinus lepideus[J].Exp Biol Med(Maywood),2003, 228(6):749-758.
[37] Reddy P. Interleukin-18: recent advances[J]. Curr Opin Hematol,2004,11(6):405- 410.
[38] Yoshimoto T and Nakanishi K. Roles of IL-18 in Basophils and Mast Cells[J]. AllergologyInternational, 2006,55:105-113.
[39] Cao R,Famebo J, Kurimoto M, et al.Interleukin-18 acts as an angiogenesis and tumor suppressor[J]. FASEB J, 1999,13(15):2195-2202.
[40] Kikuchi T, Akasaki Y, Joki T, et al. Antitumor activity of IL-18 on mouse glioma cells[J].J Immunother, 2000,23(2):184-189.
[41] Coughlin CM, Salhany KE, Wysocka M, et al.Interleukin-12 and Interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis[J]. J Clin Invest, 1998,101(6):1441- 1452.
[42] Park CC, Morel JC, Amin MA,et al.Evidence of IL-18 as a novel angiogenic medistor[J].J Immunol, 2001, 167(3):1644-1653.
[43] Kohka H,Yoshino T,Iwagaki H,et al.Interleukin-18/Interferon-gamma-ingucing factor,a novel cytokine, up-regulates ICAM-1(CD54)expression in KG-1 cells[J].J Leukoc Biol,1998,64(6):519-527.
[44] Vidal-Vanachocha F, Fantuzzi G, Mendoza L, et al.IL-18 regulates IL-1beta-dependent hepatic melanoma metastsis via vascular cell adhension molecule-1[J].Proc Natl Acad Sci USA,2000,97(2): 734-739.
[45] 钟慈声,孙安阳. 一氧化氮的生物医学[M]. 上海:上海医科大学出版社,1997 ,3 -391.
[46] Nathan C, Xie QW.Nitric oxide synthase:roles,tolls and controls.Cell,1994,78:915-918.
[47] Alderton WK,Cooper CE,Knowles RG.Nitric oxide synthase:stucture, function and inhibition[J]. Biochem J,2001,357:593-615.
[48] Sen R,Baltimore D.Mufiple nuclear fators interact with the immunoglobulin enhancer sequences[J]. Cell, 1986,46:705- 710. [49 ] Roland MS, Guido A. NF-κB /Rel/ IκB: Implications in gastrointestinal diseases[J]. Gastroentero, 2000, 118 (6) : 1208.
[50] Eric G L, David L B, Sophia C, et al. Failure to regulate TNF-induced NF-κB and cell death responses in A20deficient mice [J]. Scie, 2000, 289 (5488) : 2350.
[51] Shinichi K, Masashi S, Futoshi T, et al. Evidence that de novo protein synthesis is dispensable for antiapoptotic effects of NF-κB [J]. Oncogene, 2000, 19, (17) : 2233.
[52] Rodney WK, Anne EK and Hiary OD. Cytokine control in human endometrium[J]. Reproduction, 2001,121: 3-19.
[53] Nair A, Venkatraman M,Malieka TT, et al. NF-κB is constitutive activated in high-grade squamous intraepithelia llesions and squamous cell carcinmas of the human uterine cervix[J]. Oncogene ,2003,22: 50-58.
[54] Aradhya S, Nelson DL.NF-kappaB signaling and human disease[J]. Curr Opin Genet Dev,2001,11(3): 300- 306.
[55] Vandenbroeck K, Alloza I ,Gadina M , et al . Inhibiting cytokines of the interleukin-12 family : recent advances and novel challenges[J] . J Pharmacol ,2004 ,56 (2) :145-160.
[56] Li-weber M , Giaisi M , Baumann S , et al . NF-Kappa B Synergizes wit h NF-AT and NF-IL-6 in activation of the IL-4 gene in T-cell [J] . Eur J Immunol , 2004 ,34 (4) :1111- 1118.
[57] Das J, Chen CH, Yang L, et al . A critical role for NF-kappa B in GATA-3 expression and Th2 differentiation in allergic airway inflammation[J] . Nat Immunol ,2001 ,2 (1) :45-50.
[58] Hilliard BA, Mason N, Xu L, et al . Critical roles of C-Rel in autoimmune inflammation and helper Tcell differentiation [J] . J Clin I nvest ,2002 ,110 :843-850.
[59] Artis D, Shapira S, Mason N , et al . Differential requirement for NF-kappa B family members in cont rol of helmint h infection and intestinal inflammation[J] . J Immunol , 2002 ,169 : 4481-4487.
[60] Liou HC , Hsia CY. Distinctions between c-Rel and ot her NF-kappa B proteins in immunity and disease[J] . Bioessays , 2003 ,25 :767-780.
[61] Pai SY, Ho IC. C-Rel delivers a one-two punch in Th1 cell differentiation[J] . J Clin I nvest , 2002 , 110 : 741-742.
[62] Sha WC, Liou HC, Tuomanen EI, et al. Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses[J]. Cell, 1995, 80:321-330.
[63] Yoshimura S, Bondeson J, Brennan FM, et al. Role of NF-κB in antigen presentation and development of regulatory T cells elucidated by treatment of dendritic cells with the proteasome inhibitor PSI [J]. Eur J Immunol, 2001, 31:1883-1889.
[64] Marurno T, Schini-Kerth VB, Busse R.Vascular endothelial growth factor activates nuclear factor- kappaB and induces monocyte chemottractant protein-1 in bovine retinal endothelial cells[J].Diabetes, 1999,48(5): 1131-1138.
[65]Taniguchi M,Nagaoka K, Kunikata T, et al. Characterization of anti human interleukin-18(IL-18)/ interferon-gamma inducing factor(IGIF) monoclonal antibodies and their application in the measurement of human IL-18 by ELISA[J]. J Immonol Methods,1997,206 (1-2):107-113.
[66]Xu D, Chan WL, Leung PP, et al. Selective expression and functions of interleukin 18 receptor T helper (Th ) type 1 but not Th2 cells[J].J Exp Med,1998,188(8):1485-1492.
[67] Guilbert L. There is a bias against type 1 inflammatory cytokine expression and function in pregnancy [J]. J Reprod Immunol,1998,39:362-367.
[68] Ledee-Bataille N, Olivennes F, Kadoch J, et al. Detectable levels of interleukin-18 in uterine luminal secretions at oocyte retrieval predict failure of the embryo transfer[J]. Hum Reprod, 2004, 19(9):1968- 1973.
[69] Herington JL, Bany BM. Effect of the conceptus on uterine natural killer cell numbers and function in the mouse uterus during decidualization[J].Biol Reprod,2007 ,76(4):579-588.
[70] Laskarin G, Strbo N, Bogovic Crncic T, et al. Physiological role of IL-15 and IL-18 at the maternal- fetal interface[J]. Chem Immunol Allergy. 2005,89:10- 25.
[71] Tokmadzic VS, Tsuji Y, Bogovic T, et al. IL-18 is present at the maternal-fetal interface and enhances cytotoxic activity of decidual lymphocytes[J]. Am J Reprod Immunol,2002,48(4): 191- 200.
[72] Xie X, He H, Colonna M, et al. Pathways participating in activation of mouse uterine natural killer cells during pregnancy[J]. Biol Reprod,2005 ,73(3):510-518.
[73] Lédée N, Dubanchet S, Lombroso R, et al. Downregulation of human endometrial IL-18 by exogenous ovarian steroids[J].Am J Reprod Immunol, 2006,56(2):119-123.
[74] Sakai M, Shiozaki A, Sasaki Y, et al.The ratio of interleukin (IL)-18 to IL-12 secreted by peripheral blood mononuclear cells is increased in normal pregnant subjects and decreased in pre-eclamptic patients[J]. J Reprod Immunol,2004,61(2):133-143.
[75] 王春,尚涛.IL-18与妊娠、分娩关系的研究[J].中华临床医药,2002,3(23): 27-28.
[76] Ida A, Tsuji Y, Muranaka J, et al. IL-18 in pregnancy: the elevation of IL-18 in maternal peripheral blood during labour and complicated pregnancies[J]. J Reprod Immunol, 2000,47(1):65-74.
[77] Mansouri R, Akbari F, Vodjgani M, et al..Serum cytokines profiles in Iranian patients with preeclampsia[J]. Iran J Immunol. 2007 ,4(3):179-185.
[78] Huang XD, Huang HF, Dong MY, et al. Relationship between serum and placental interleukin-18 levels and preeclampsia[J].Zhejiang Da Xue Xue Bao Yi Xue Ban,2005,34(6): 495-498.
[79] Wang X, Hagberg H, Mallard C, et al. Disruption of interleukin-18, but not interleukin-1, increases vulnerability to preterm delivery and fetal mortality after intrauterine inflammation[J].Am J Pathol ,2006,169(3):967-976.
[80] Wilson R, Jenkins C, Miller H, et al. Abnormal cytokine levels in non-pregnant women with a history of recurrent miscarriage[J]. Eur J Obstet Gynecol Reprod Biol, 2004,115(1):51-54.
[81] Tesfaye D, Kadanga A, Rings F, et al. The effect of nitric oxide inhibition and temporal expression patterns of the mRNA and protein products of nitric oxide synthase genes during in vitro development of bovine pre-implantation embryos[J]. Reprod Domest Anim, 2006 ,41(6):501-509.
[82] Zhang X, Lin HY, Liu GY, et al. Expressions and regulation of endothelial and inducible nitric oxide synthases in mouse uterus during the estrous cycle and early pregnancy[J]. Front Biosci, 2005,10(9): 3172-3182.
[83] Okawa T, Asano K, Takahashi H, et al. Expression of inducible nitric oxide synthase messenger RNA, but not guanylate cyclase messenger RNA, depends on gestational age in rat myometrium[J]. Gynecol Endocrinol, 2004,19(3): 146-151.
[84] Vaisanen-Tommiska M, Butzow R, et al. Mifepristone-induced nitric oxide release and expression of nitric oxide synthases in the human cervix during early pregnancy[J]. Hum Reprod.,2006 21(8): 2180-2184.
[85] Aalberts M, van Dissel-Emiliani FM, van Tol HT, et al. High iNOS mRNA and protein levels during early third trimester suggest a role for NO in prelabor cervical ripening in the bovine[J]. Mol Reprod Dev, 2007 , 4(3):378-385.
[86] 王山米,许艳,虞有智.妊娠晚期和分娩期诱导型一氧化氮合酶在子宫下段及胎盘的定位与活性观察[J].中国实用妇科与产科杂志,2002,18(11):670-672.
[87] 王俊梅,宋明清,刘斌.诱生型一氧化氮合酶抑制剂氨基胍对鼠胚发育的影响[J].北京大学学报( 医学版), 2001,33(2):153-156.
[88] Cella M, Aisemberg J, Sordelli MS, et al. Prostaglandins modulate nitric oxide synthase activity early in time in the uterus of estrogenized rat challenged with lipopolysaccharide[J]. Eur J Pharmacol, 2006 ,534(1-3):218-226.
[89] 张育新,潘维梅,赵春丽.一氧化氮在妊高征发病机理中的作用[J].齐齐哈尔医学院学报,2001,22(7):755-757.
[90] 林晓娟,严亚迎,高英敏.诱导型一氧化氮合酶和P 选择素在早期自然流产中的表达及临床意义[J].生殖医学,中国生育健康杂志,2004,15(2):92-95.
[91] Tornblom SA, Maul H, Klimaviciute A,et al.mRNA expression and localization of bNOS, eNOS and iNOS in human cervix at preterm and term labour[J]. Reprod Biol Endocrinol,2005, 10(3):33.
[92] Schiessl B, Mylonas I, Hantschmann P,et al. Expression of endothelial NO synthase, inducible NO synthase, and estrogen receptors alpha and beta in placental tissue of normal, preeclamptic, and intrauterine growth-restricted pregnancies[J]. J Histochem Cytochem., 2005 ,53(12):1441-1449.
[93] 谢青贞,辛志敏.核因子-κB与生殖调节[J].国外医学妇产科学分册,2002,29(4):223-225.
[94] Nakamura H, Kimura T, Ogita K, et al. Alteration of the timing of implantation by in vivo gene transfer: delay of implantation by suppression of nuclear factor kappaB activity and partial rescue by leukemia inhibitory factor[J].Biochem Biophys Res Commun,2004, 321 (4):886-892.
[95] Muggia A, Teesalu T, Neri A, et al. Trophoblast giant cells express NF- kappaB2 during early mouse development[J] . Dev Ge-net ,1999,25:23-30.
[96] Allport VC, Pieber D, Slater DM, et al. Human labour is associated with nuclear factor kappaB activity uhich mediates cyclooxygenase-2 expression and is involved with the ’functional prgesterone withdrawal’ [J]. Mol Hum Reprod , 2001 ,7 :581-586.
[97] Goebeler M, Gillitzer R , Kilian K, et al. Multiple sigaling pathways regulate NF-kappa B-dependent transcription of the monocyte chemoattractant protein -1 gene in primary endothelial cells [J ] . Blood , 2001 , 97(1) :46-55.
[98] 曲鑫,张树泉,姜学强,等.核因子κB及黏附分子在妊娠高血压综合征患者胎盘组织中的表达[J]. 中华妇产科杂志2005,40(10):701-703.
[99] Schmitz T, Souil E, Hervé R, et al. PDE4 inhibition prevents preterm delivery induced by an intrauterine inflammation[J ].J Immunol, 2007, 178(2):1115- 1121.
[100] Shah TJ, Walsh SW. Activation of NF-kappaB and expression of COX-2 in association with neutrophil infiltration in systemic vascular tissue of women with preeclampsia[J]. Am J Obstet Gynecol, 2007 ,196 (1):48:1-8.
[101] 张宁,徐永健,张珍祥,等.一氧化氮-核因子-κB信号通路在支气管哮喘患者T细胞功能表达中的作用[J].中华内科杂志,2005,44(5):328-332.
[102] 张宁.一氧化氮对核因子-κB的反馈调节作用[J].国外医学呼吸系统分册,2002,22 (2):66- 69.
[103] Andre R, Wheeler RD, Collins PD, et al. Identification of a truncated IL-18R beta mRNA: a putative regulator of IL-18 expressed in rat brain[J]. J Neuroimmunol,2003,145(1-2):40-45
[104] Culhane AC, Hall MD, Rothwell NJ, et al. Cloning of rat brain interleukin-18 cDNA[J]. Mol Psychiatry, 1998 ,3(4):362-366.
[105] Wang N, Sugama S, Conti B, et al. Interleukin-18 mRNA expression in the rat pituitary gland[J]. J Neuroimmunol, 2006,173(1-2):117-125.
[106] Nagai Y, Nochi T, Watanabe K, et al. Localization of interleukin-18 and its receptor in somatotrophs of the bovine anterior pituitary gland[J]. Cell Tissue Res, 2005,322(3):455- 462.
[107] Nagai Y, Watanabe K, Aso H, et al. Cellular localization of IL-18 and IL-18 receptor in pig anterior pituitary gland[J]. Domest Anim Endocrinol, 2006,30(2):144-154.
[108] Tsuji Y, Tamaoki TH, Hasegawa A, et al. Expression of interleukin-18 and its receptor in mouse ovary[J]. Am J Reprod Immunol, 2001,46(5):349-357.
[109] Gutman G, Soussan-Gutman L, Malcov M, et al. Interleukin-18 is high in the serum of IVF pregnancies with ovarian hyperstimulation syndrome[J]. Am J Reprod Immunol, 2004 ,51(5): 381- 394.
[110] Murakami Y, Otsuki M, Kusumoto K, et al. Estrogen inhibits interleukin-18 mRNA expression in the mouse uterus[J]. J Reprod Dev, 2005,51(5):639-647.
[111] Ida A, Tsuji Y, Muranaka J, et al. IL-18 in pregnancy; the elevation of IL-18 in maternal peripheral blood during labour and complicated pregnancies[J]. J Reprod Immunol, 2000 May;47(1):65-74.
[112] 胡昌东,归绥琪.自然流产患者滋养细胞肝素表皮生长因子的表达和意义[J].上海医学,2004,27(7):491- 494.
[113] 吴浩,常雅萍,于永利.Th1 型/Th2 型细胞因子与妊娠的免疫调节[J].国外医学.免疫学分册,1999:22(2):57-66.
[114] Culhane AC, HallMD, RothwellNJ, et al. Cloning of rat brain interleukin-18 cDNA[J]. Mol Psychiatry, 1998, 3 (4) : 362-366.
[115]Sugama, S,Cho BP, Baker H, et al. Neurons of the superior nucleus of the medial habenula and ependymal cells express IL-18 in rat CNS[J]. Brain Res, 2002,958(1):1–9.
[116]Andre R, Wheeler RD, Collins PD, et al. Identification of a truncated IL-18R beta mRNA: a putative regulator of IL-18 expressed in rat brain[J]. J Neuroimmunol,2003 ,145(1-2):40-55.
[117] Sugama S, Fujita M, Hashimoto M, et al. Stress induced morphological microglial activation in the rodent brain: involvement of interleukin-18[J]. Neuroscience , 2007, 146(3): 1388-1399.
[118] Koibuchi N , Fujita M , Hashimoto M , et al. The adrenal gland is a source of stress-induced circulating IL-18[J].Journal of Neuroimmunology, 2006,172:59-65.
[119] Wang N, Sugama S, Conti B, et al. Interleukin-18 mRNA expression in the rat pituitary gland[J]. J Neuroimmunol ,2006 ,173(1-2):117-125.
[120] Igaz P, Salvi R, Rey JP, et al.Effects of Cytokines on Gonadotropin- Releasing Hormone (GnRH) Gene Expression in Primary Hypothalamic Neurons and in GnRH Neurons Immortalized Conditionally[J]. Endocrinology , 2006,147(2):1037-1043.
[121]Yamaguchi M, Koike K, Yoshimoto Y, et al. Interleukin-6 stimulates gonadotropin- releasing hormone secretion from rat hypothalamic cells[J]. Horm Res,1991,35:252-256
[122] Yamaguchi M, Yoshimoto Y, Komura H, et al. Interleukin 1β and tumour necrosis factor αstimulate the release of gonadotropin-releasing hormone and interleukin 6 by primary cultured rat hypothalamic cells[J]. Acta Endocrinol (Copenh), 1990,123:476-480.
[123] Kang SS, Kim SR, Leonhardt S, et al. Effect of interleukin-1βon gonadotropin- releasing hormone (GnRH) and GnRH receptor gene expression in castrated male rats[J]. J Neuroendocrinol, 2000,12: 421- 429.
[124] Feleder C, Arias P, Refojo D, et al. Interleukin-1 inhibits NMDA-stimulated GnRH secretion: associated effects on the release of hypothalamic inhibitory amino acid neurotransmitters[J]. Neuroimmuno- modulation,2000, 7:46-50.
[125]Kanno T, Nagata T, Yamamoto S, et al. Interleukin-18 stimulates synaptically released glutamate and enhances postsynaptic AMPA receptor responses in the CA1 region of mouse hippocampal slices[J]. Brain Res ,2004,1012(1-2):190-193.
[126] Schneider, E. Pro-Th1 cytokines promote Fas-dependent apoptosis of immature peripheral basophils[J]. J Immunol,2004,172:5262-5268.
[127] Chandrasekar, B. Activation of intrinsic and extrinsic pro-apoptotic signaling pathways in interleukin-18-mediated human cardiac endothelial cell death[J]. J Biol. Chem, 2004,279:20221- 20233.
[128] Finotto, S. Severe hepatic injury in interleukin-18 (IL-18) transgenic mice: a key role for IL-18 in regulating hepatocyte apoptosis in vivo[J]. Gut ,2004 , 53:392-400.
[129] Bushley AW,Ferrell R,Mcduffie K,et al.Polymorphisms of interleukin(IL)-1alpha, IL-1beta, IL-6,IL-10 and IL-18 and the risk of ovarian cancer[J]. Gynecol Oncol,2004,95(3):672-679.
[130] Pitzel L, Jarry H and Wuttke W. Effects and interactions of prostaglandin , oxytocin and cytokines on steroidogenesis of porcine luteal cells[J]. The Endocrine Society ,1993,132 (2 ): 751-756.
[131] Vujisic S, Lepej SZ, Emedi I, et al. Ovarian follicular concentration of IL-12, IL-15, IL-18 and p40 subunit of IL-12 and IL-23 [J]. Hum Reprod, 2006 , 21 (10):2650-2655.
[132] Huck B, Steck T, Habersack M, et al. Pregnancy associated hormones modulate the cytokine production but not the phenotype of PBMC- derived human dendritic cells[J]. Eur J Obstet Gynecol Reprod Biol, 2005,122(1):85-94.
[133] Lédée N, Dubanchet S, Lombroso R, et al. Downregulation of human endometrial IL-18 by exogenous ovarian steroids. Am J Reprod Immunol, 2006 ,56(2):119-123.
[134] Ledee-Bataille N, Dubanchet S, Coulomb-L'hermine A, et al.A new role for natural killer cells, interleukin (IL)-12, and IL-18 in repeated implantation failure after in vitro fertilization [J]. Fertility and Sterility,2004,81(1): 59-65.
[135] Luo Q, Ning WX, Wu YT, et al.Altered expression of interleukin-18 in the ectopic and eutopic endometrium of women with endometriosis [J]. Journal of Reproductive Immunology,2006,72 (1-2):108-117.
[136] Zhang JH, He H, Borzychowski AM., et al. Analysis of Cytokine Regulators Inducing Interferon Production by Mouse Uterine Natural Killer Cells [J]. Biology of Reproduction, 2003,69(2):404-411.
[137] Chaouat G, Zourbas S, Ostojic S, et al. A brief review of recent data on some cytokine expressions at the materno-foetal interface which might challenge the classical Th1/Th2 dichotomy[J] . Journal of Reproductive Immunology, 2002, 53(1-2): 241-256.
[138] Rivier C. Role of gaseous neurotransmitters in the hypothalamic-pituitary- adrenal axis[J]. Ann N Y Acad Sci, 2001,933:254-264.
[139] Wood CE, Giroux D. Expression of nitric oxide synthase isoforms in the ovine fetal brain: alteration by hormonal and hemodynamic stimuli[J]. J Soc Gynecol Investig, 2006 ,13(5): 329-337.
[140] Akasaka S, Nomura M, Nishii H, et al. The hypothalamo-pituitary axis responses to lipopolysaccharide-induced endotoxemia in mice lacking inducible nitric oxide synthase[J]. Brain Res, 2006,1089(1):1-9.
[141] Ca?ka J. The role of nitric oxide in the hypothalamic control of LHRH and oxytocin release, sexual behavior and aging of the LHRH and oxytocin neurons[J]. Folia Histochem Cytobiol. 2006;44(1): 3-12.
[142] Grange-Messent V, Raison D, Dugas B, et al. Noradrenaline up-regulates the neuronal and the inducible nitric oxide synthase isoforms in magnocellular neurons of rat brain slices[J]. Calas A. J Neurosci Res, 2004 ,78(5):683-690.
[143] Kjeldsen TH, Rivier C, Lee S, et al.Inducible nitric oxide synthase is responsible for nitric oxide release from murine pituicytes[J]. J Neuroendocrinol, 2003 ,15(3): 250-255.
[144] Mccann SM, Kimura M, Karanth S, et al.The Mechanism of Action of Cytokines to Control the Release of Hypothalamic and Pituitary Hormones in Infection[J] . Annals of the New York Academy of Sciences, 2000,917:4-18.
[145] Uretsky AD, Weiss BL, Yunker WK, et al.Nitric oxide produced by a novel nitric oxide synthase isoform is necessary for gonadotropin-releasing hormone- induced growth hormone secretion via a cGMP- dependent mechanism[J]. J Neuroendocrinol, 2003,15(7):667-676.
[146] Kim H, Moon C, Ahn M, et al. Expression of nitric oxide synthase isoforms in the porcine ovary during follicular development. J Vet Sci[J], 2005,6(2):97-101.
[147] Matsumi H, Yano T, Osuga Y, et al. Regulation of nitric oxide synthase to promote cytostasis in ovarian follicular development[J]. Biol Reprod, 2000 ,63(1):141-146.
[148] Mitchell LM, Kennedy CR, Hartshorne GM. Expression of nitric oxide synthase and effect of substrate manipulation of the nitric oxide pathway in mouse ovarian follicles[J]. Hum Reprod, 2004,19(1):30-40.
[149] Chen Q, Yano T, Matsumi H, et al. Cross-Talk between Fas/Fas ligand system and nitric oxide in the pathway subserving granulosa cell apoptosis: a possible regulatory mechanism for ovarian follicle atresia[J]. Endocrinology, 2005,146(2):808-815.
[150] Gay-Andrieu F, Cozon GJ, Ferrandiz J, et al. Progesterone fails to modulate Toxoplasma gondii replication in the RAW 264.7 murine macrophage cell line[J]. Parasite Immunol. 2002,24(4): 173-178.
[151] Rosiansky-Sultan M, Klipper E, Spanel-Borowski K, et al. Inverse relationship between nitric oxide synthases and endothelin-1 synthesis in bovine corpus luteum: interactions at the level of luteal endothelial cell[J]. Endocrinology, 2006,147(11):5228-5235.
[152] Boiti C, Zampini D, Guelfi G, et al. Expression patterns of endothelial and inducible nitric oxide synthase isoforms in corpora lutea of pseudopregnant rabbits at different luteal stages [J]. J Endocrinol, 2002,173 (2):285-296.
[153] Hurwitz A, Finci-Yeheskel Z, Milwidsky A, et al. Regulation of cyclooxygenase activity and progesterone production in the rat corpus luteum by inducible nitric oxide synthase[J]. Reproduction, 2002,123(5):663-669.
[154] Tobai H, Nishiya I. Nitric oxide mediates inhibitory effect of interleukin-1beta on estrogen production in human granulosa-luteal cells[J]. J Obstet Gynaecol Res, 2001 ,27(1):53-59.
[155] Gay-Andrieu F, Cozon GJ, Ferrandiz J, et al. Progesterone fails to modulate Toxoplasma gondii replication in the RAW 264.7 murine macrophage cell line[J]. Parasite Immunol, 2002 ,24(4): 173-178.
[156] Yang H, Bhat GK, Wadley R, et al. Gonadotropin-releasing hormone-agonist inhibits synthesis of nitric oxide and steroidogenesis by luteal cells in the pregnant rat[J]. Biol Reprod, 2003,68(6): 2222-2231.
[157] Zhang X, Lin HY, Liu GY, et al. Expressions and regulation of endothelial and inducible nitric oxide synthases in mouse uterus during the estrous cycle and early pregnancy[J]. Front Biosci, 2005,10: 3172- 3182.
[158] Welter H, Bollwein H, Weber F, et al. Expression of endothelial and inducible nitric oxide synthases is modulated in the endometrium of cyclic and early pregnant mares[J]. Reprod Fertil Dev, 2004,16(7): 689-698.
[159] Burnett TG, Hunt JS. Nitric oxide synthase-2 and expression of perforin in uterine NK cells [J]. J Immunol, 2000 ,164(10):5245-5250.
[160] Okada Y, Asahina T, Kobayashi T, et al. Studies on the mechanism of edematous changes at the endometrial stroma for implantation[J]. J Immunol, 2001;27(2):67-77..
[161] Burnett TG, Tash JS, Hunt JS. Investigation of the role of nitric oxide synthase in pregnancy usingmutant mice[J]. Reproduction. 2002,124(1):49-57.
[162] Kwon H, Wu G, Meininger CJ, et al. Developmental changes in nitric oxide synthesis in the ovine placenta[J]. Biol Reprod, 2004 ,70(3):679-686.
[163] Farina M, Ribeiro ML, Franchi A. Nitric oxide synthases in pregnant rat uterus[J]. Reproduction, 2001, 121(3):403-407.
[164] Yallampalli C, Dong YL. Estradiol-17beta inhibits nitric oxide synthase (NOS)-II and stimulates NOS-III gene expression in the rat uterus[J]. Biol Reprod, 2000,63(1):34-41.
[165]Mccracken SA, Gallery E, Morris JM.Pregnancy-specific down-regulation of NF-kappa B expression in T cells in humans is essential for the maintenance of the cytokine profile required for pregnancy success[J]. J Immunol,2004,172(7):4583-4591.
[166] Gonzalez-Navarrete F, Eisner V, Morales P, et al. Tumor necrosis factor-alpha activates nuclear factor- kappaB but does not regulate progesterone production in cultured human granulosa luteal cells[J]. Gynecol Endocrinol, 2007,23(7):377-384.
[167] Diamanti-Kandarakis E, Piperi C, Patsouris E, et al. Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries[J]. Histochem Cell Biol, 2007,127(6):581-589.
[168] Chu S, Nishi Y, Yanase T, et al. Transrepression of estrogen receptor beta signaling by nuclear factor- kappab in ovarian granulosa cells[J]. Mol Endocrinol, 2004 ,18(8):1919- 1928.
[169] Valdez KE, Turzillo AM. Regulation of nuclear factor-kappaB (NF-kappaB) activity and apoptosis by estradiol in bovine granulosa cells[J]. Mol Cell Endocrinol, 2005 ,243(1-2):66- 73.
[170] Kelly RW, King AE, Critchley HO. Cytokine control in human endometrium[J]. Reproduction, 2001,121(1):3-19.
[171] Son DS, Roby KF. Interleukin- 1alpha-induced chemokines in mouse granulosa cells: impact on keratinocyte chemoattractant chemokine, a CXC subfamily[J]. Mol Endocrinol. 2006,20(11):2999- 3013.
[172] Xiao CW, Asselin E, Tsang BK. Nuclear factor kappaB-mediated induction of Flice-like inhibitory protein prevents tumor necrosis factor alpha-induced apoptosis in rat granulosa cells[J]. Biol Reprod, 2002 ,67(2):436-441.
[173] Telleria CM, Goyeneche AA, Stocco CO, et al. Involvement of nuclear factor kappa B in the regulation of rat luteal function: potential roles as survival factor and inhibitor of 20 alpha-hydroxysteroid dehydrogenase[J]. J Mol Endocrinol, 2004 ,32(2):365-383.
[174] Martin R D , Hoeth M , Hofer-Warbinek R. The Transcription Factor NF-kB and the Regulation of Vascular Cell Function[J]. Arterioscler Thromb Vasc Biol,2000,20(11): 83- 88.
[175] van der Burg B, van der Saag PT. Nuclear factor-kappa-B/steroid hormone receptor interactions as a functional basis of anti-inflammatory action of steroids in reproductive organs[J]. Mol Hum Reprod, 1996,2(6):433-438.
[176] Xie Q, Xin Z, Cao L, et al. Expression of nuclear factor-kappaB in mouse uterus during peri-implantation [J]. J Huazhong Univ Sci Technolog Med Sci, 2004,24(4):361-364.
[177] Geisert RD, Ross JW, Ashworth MD, et al. Maternal recognition of pregnancy signal or endocrine disruptor: the two faces of oestrogen during establishment of pregnancy in the pig[J]. Endocrinology, 2007,148: 4761-4773.
[178] King AE, Critchley HO, Kelly RW. The NF-kappaB pathway in human endometrium and first trimester decidua[J]. Mol Hum Reprod, 2001,7(2):175-183.
[179] Nakamura H, Kimura T, Ogita K, et al.NF-kappaB activation at implantation window of the mouse uterus[J]. Am J Reprod Immunol, 2004 ,51(1):16-21.
[180] Mccracken SA, Hadfield K, Rahimi Z, et al. NF-kappaB-regulated suppression of T-bet in T cells represses Th1 immune responses in pregnancy[J]. Eur J Immunol. 2007 May;37(5): 1386-1396.
[181] Mccracken SA, Gallery E, Morris JM. Pregnancy-specific down-regulation of NF-kappa B expression in T cells in humans is essential for the maintenance of the cytokine profile required for pregnancy success [J]. J Immunol, 2004,172(7):4583-4591.
[182] Lappas M, Permezel M, Holdsworth SJ, et al. Antiinflammatory effects of the cyclopentenone isoprostane 15-A(2)-IsoP in human gestational tissues[J]. Free Radic Biol Med, 2007,42(12): 1791-1796.
[183] Mendelson CR, Condon JC. New insights into the molecular endocrinology of parturition[J]. J Steroid Biochem Mol Biol, 2005,93(2-5):113-119.
[184] Shimizu S, Tahara M, Ogata S, et al. Involvement of nuclear factor-kB activation through RhoA/ Rho- kinase pathway in LPS-induced IL-8 production in human cervical stromal cells [J]. Mol Hum Reprod, 2007,13(3):181-187.
[185] Condon JC, Hardy DB, Kovaric K, et al. Up-regulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear factor-kappaB may contribute to the onset of labor through inhibition of PR function. Mol Endocrinol[J]. 2006 ,20(4):764- 775.
[186] Dosiou C, Giudice LC. Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives[J]. Endocrine,2000,26(1):44-62.
[187] 唐薇.米非司酮终止妊娠的分子免疫机制[J].海南医学,2005,16(3):124-126.
[188] Gruber CJ, Huber JC. The role of dydrogesterone in recurrent abortion[J]. J Steroid Biochen Mol Biol, 2005,97 (5):426-430.
[189] Ostoji? S, Volk M, Medica I,et al. Polymorphisms in the interleukin-12/18 genes and recurrent spontaneous abortion[J]. Am J Reprod Immunol. 2007 ,58(5):403-408.
[190] Mansouri R, Akbari F, Vodjgani M,et al.Serum cytokines profiles in Iranian patients with preeclampsia [J]. 2007 ,4(3):179-185.
[191] Gracie JA, Robertson SE, McInnes IB. Interleukin-18[J]. J Leukoc Biol, 2003,73:213–224.
[192] Andrea R, Wheelerb RD, Collinsa PD, et al. Identification of a truncated IL-18Rh mRNA: a putative regulator of IL-18 expressed in rat brain[J]. Journal of Neuroimmunology , 2003, 145:40–45.
[193] Felderhoff-Mueser U ,Schmidt OI, Oberholzer A, et al. IL-18: a key player in neuroinflammation and neurodegeneration[J].Trends in Neurosciences, 2005,28(9):487- 493.
[194] Kanno, T. Interleukin-18 stimulates synaptically released glutamate and enhances postsynaptic AMPA receptor responses in the CA1 region of mouse hippocampal slices[J]. Brain Res, 2004,1012:190–193.
[195] Zhang YF, Yang YS, Hong J, et al. Elevated serum levels of interleukin-18 are associated with insulin resistance in women with polycystic ovary syndrome[J]. Endocrine, 2006 ,29(3):419-423.
[196]Sarkar NN. The potential of mifepristone (RU486) as a female contraceptive drug[J]. Int J Clin Pract , 2002 , 56 (2) :140-144.
[197] Naeimi S, Ghiam A F, Mojtahedi Z, et al. Interleukin-18 gene promoter polymorphisms and recurrent spontaneous abortion[J]. Eur J Obstet Gynecol Reprod Biol, 2006,128(1-2): 5- 9.
[198] Zicari A, Ticconi C, Ietta F, et al. Macrophage migration inhibitory factor-nitric oxide interaction in human fetal membranes at term pregnancy[J]. J Soc Gynecol Investig ,2006 , 13(4):263-270.
[199] Wang C, Hikim AS, Ferrini M, et al. Male reproductive ageing: using the brown Norway rat as a model for man[J]. Novartis Found Symp,2002,242:82-95.
[200] Gonzalez-Cadavid NF, Swerdloff RS, Ferrini M, et al. Aging-related increased expression of inducible nitric oxide synthase and cytotoxicity markers in rat hypothalamic regions associated with male reproductive function[J]. Neuroendocrinology,2001,74(1):1-11. [ 201] Dingman A, Lee SY, Derugin N, et al. Aminoguanidine inhibits caspase-3 and calpain activation without affecting microglial activation following neonatal transient cerebral ischemia[J]. J Neurochem,2006, 96(5):1467-1479.
[202] Neuvians TP, Schams D, Berisha B, et al. Involvement of pro-inflammatory cytokines, mediators of inflammation, and basic fibroblast growth factor in prostaglandin F-alpha-induced luteolysis in bovine corpus luteum[J]. Biol Reprod,2004, ,70(2):473-480.
[203] Mitchell LM, Kennedy CR, Hartshorne GM.Expression of nitric oxide synthase and effect of substrate manipulation of the nitric oxide pathway in mouse ovarian follicles[J]. Hum Reprod, 2004 ,19(1):30-40.
[204] Sundaresan NR, Saxena VK, Sastry KV, et al. Nitric oxide: a possible mediator of ovulation and postovulatory follicle regression in chicken[J]. Anim Reprod Sci, 2007 ,101(3-4):351- 357.
[205] Casais M, Delgado SM, Vallcaneras S, et al. Nitric oxide in prepubertal rat ovary contribution of the ganglionic nitric oxide synthase system via superior ovarian nerve[J]. Neuro Endocrinol Lett,2007,28(1): 39-44.
[206] Okawa T, Asano K, Takahashi H, et al. Expression of inducible nitric oxide synthase messenger RNA, but not guanylate cyclase messenger RNA, depends on gestational age in rat myometrium[J]. Gynecol Endocrinol , 2004 ,19(3):146-51.
[207] Baylis SA, Strijbos PJ, Sandra A, et al. Temporal expression of inducible nitric oxide synthase in mouse and human placenta[J]. Mol Hum Reprod,1999,5(3):277-286.
[208] Zhang X, Lin HY, Liu GY, et al. Expressions and regulation of endothelial and inducible nitric oxide synthases in mouse uterus during the estrous cycle and early pregnancy[J]. Front Biosci ,2005,10: 3172- 3182.
[209]Emanuela M, Iorio D, Romolo, et al. Adrenomedullin and nitric oxide synthase at the maternal- decidual interface in early spontaneous abortion[J].Journal of Reproductive Medicine,2004, 49 (3): 153-161.
[210] Kwon H, Wu G, Meininger CJ, et al.Developmental changes in nitric oxide synthesis in the ovine placenta[J].Biol Reprod,2004, 70(3):679-686.
[211] 沈政,铁国栋,赵兴绪,等.雌性动物生殖系统中的一氧化氮[J].细胞生物学杂志, 2004,26: 349-351.
[212] Marinoni E, Di Iorio R, Villaccio B, et al.Amniotic fluid nitric oxide metabolite levels and nitric oxide synthase localization in feto-placental tissues are modified in association with human labor[J]. Eur J Obstet Gynecol Reprod Biol,2000, 89(1):47-54.
[213] Jiang RZ, Huang YJ, Gu JH, et al.Effects of nuclear factor-kappaB decoy oligodeoxynucleotide onthe function of human umbilical artery smooth muscle cells induced by umbilical sera in preeclampsia[J]. Zhonghua Fu Chan Ke Za Zhi,2007,42(2):87- 91.
[214] Martin RD, Hoeth M, Hofer-Warbinek R, et al. The Transcription Factor NF-kB and the Regulation of Vascular Cell Function[J].Arterioscler Thromb Vasc Biol,2000,20(11): 83-88.
[215] Gao GL, Liu LD, Zou XS, Chen WX. Expression of KiSS-1, matrix metalloproteinase-9, nuclear factor-kappaBp65 in ovarian tumour[J]. Zhonghua Fu Chan Ke Za Zhi,2007, 42(1): 34-38.
[216] Diamanti-Kandarakis E, Piperi C, Patsouris E, et al.Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries[J]. Histochem Cell Biol, 2007, 127(6):581-589.
[217] 郑仲谨,李磊.核转录因子κB在全身炎症反应综合征中的作用[J].免疫学杂志,2001, 17(4):314-317.
[218] Valdez KE, Turzillo AM. Regulation of nuclear factor-kappaB (NF-kappaB) activity and apoptosis by estradiol in bovine granulosa cells[J]. Mol Cell Endocrinol,2005, 243(1-2):66- 73.
[219] Li MJ, Li JJ, Zhao XB, et al. Influence of mifepristone and lilopristone on proliferation and expression of nuclear factor-kappa B of ectopic stromal cells in vitro[J]. Zhonghua Fu Chan Ke Za Zhi,2005, 40(1):21-24.
[220] Wang Y, Chan S, Tsang BK. Involvement of inhibitory nuclear factor-kappaB (NFkappaB)- independent NFkappaB activation in the gonadotropic regulation of X-linked inhibitor of apoptosis expression during ovarian follicular development in vitro[J]. Endocrinology,2002 ,143(7):2732-2740.
[221] Xiao CW, Asselin E, Tsang BK. Nuclear factor kappaB-mediated induction of Flice-like inhibitory protein prevents tumor necrosis factor alpha-induced apoptosis in rat granulosa cells[J]. Biol Reprod, 2002, 67(2):436-441.
[222] Reznikov LL, Shames BD, Barton HA , et al.Interleukin-1β deficiency results in reduced NF-kB levels in pregnant mice[J].Am J Physiol Regulatory Integrative Comp Physiol, 2000, 278:263-270. .
[2] 胡冬梅,陈竹钦,曹咏清.蜕膜细胞成分及其免疫生物学特性的研究进展[J].生殖与避孕,1998,18(3):131-135.
[3] 胡冬梅,陈竹钦,颜建华,等.正常早孕蜕膜非免疫细胞免疫活性的实验研究[J].中华妇产科杂志,1999,34(9):533-535.
[4] Olivares EG, Montes MJ, Oliver C, et a1.Cultured human decidual stromal cells express B7-1(CDS0) and B7-2(CD86)and stimulate al!ogeneic T cells[J].Biol Reprod,1997,57: 609- 615.
[5] Imaik K, Maeda M, Fujiwara H, et al.Human endometrial stromal cells and decidual cell express cluster of differentiation (CD)13 antigen/amninopeptidase N and CD10 antigen/neutral endopeptidase[J].Biol Reprod,1992,46:328-334.
[6] Raghupathy R. Th1-type immunity is incompatible with successful pregnancy [J]. Immunol Today, 1997,18 (10):478-482
[7] Wilczynski JR, Tchorzewski H, Banasik M, et al. Lymphocyte subset distribution and cytokine secretion in third trimester decidua in normal pregnancy and preeclampsia[J]. Eur J Obstet Gynecol Reprod Biol, 2003, 109(1):8-15.
[8] Hossein H, Mahroo M, Abbas A, et al. Cytokine production by peripheral blood mononuclear cells in recurrent miscarriage[J]. Cytokine, 2004,28(2):83-86.
[9] Daher S, de-Arruda-Geraldes-Denardi K, Blotta MH, et al. Cytokines in recurrent pregnancy loss[J]. J Reprod Immunol, 2004, 62 (1-2): 151-157.
[10] Somi S S.Cytokines during early pregnancy mammals[J].Anim Reprod sci,2003,75:73-94.
[11] Piccinni MP, Scaletti C, Vultaggio A, et a1. Defective production of ILF,M-CSF and Th2-type cytokines by T ceils at fetomaternal interface is associated with pregnancy loss[J].J Reprod Immunol, 2001, 52:35- 43.
[12] Hunt JS, Petroff MG, Burneff TG.Uterine leukocytes:key player in pregnancy[J].Cell and Develop Biol, 2000,11:127-137.
[13] Somi SS.Cytokines during early pregnancy mammals [J].Anim Reprod sci,2003,75:73-94.
[14] Uckan D, Steele A, Cherry B, et al. Trophoblasts expression Fas ligand : A proposed mechanism for immune privilege in placenta and maternal invasion[J] . Mol Hum Reprod, 1997,3 (8) :655 – 662.
[15] Hammer A, Dohr G. Expression of Fas-ligand in first trimester and term human placental villi [J] . J Reprod Immunol, 2000, 46 (2) : 83 -90.
[16] Eis A, Myatt L, Brockman DE, et al. Inducible (type Ⅱ) nitric oxide synthase in human placental villous tissue of normotensive pre-ellamptic and intranterine growth-restricted pregnancies[J] . AmJ Reprod Immunol, 1997, 38 (4) :289-294.
[17] Clark DA , Keil A ,Chen Z ,et al. Placental trophoblast from successful human pregnancies expresses the tolerance signaling molecule , CD200 (OX-2) [J] . Am J Reprod Immunol , 2003,50 (3) :187–195.
[18] Veen RC, Roberts LJ. Nitric Oxide Synthase Expression and NitricOxide [J] .Toxicity in Oligodendro- cytes Cell Immunol, 1999, 193 (2) :194-201.
[19] Odamura H, Tsutsi H, Komatsu T, et al. Cloning of a new cytokine that induces IFN-gamma Production by T cell[J].Nature,1995,378(6552):88-91 .
[20] Nakamura K, Okamura H, Nagata K, et al. Purification of a factor which provides a costimulatory signal for gamma interferon production[J].Infect Immunol,1993,61 (1): 64.
[21] Okamura H, Nagata K, Komatsu H, et al. A novel costimulatory factor for gamma interferon induction found in the livers of minusc ausese ndotoxic shock[J]. Infect Immune,1995,63 (10):3966.
[22] Ushio S, Namba M,Okura T, et al. Cloning of the cDNA for human IFN gamma-inducing factor, Expressionin Escherichia coli, and studies on the biologic actifities of the protein[J].J Immunol,1996,156(11):4274-4279.
[23] Kawakami K.Interleukin-18 and host defense against infectious pathogens[J].J Immunother, 2002,25 (suppl 1):512-519.
[24] Park H,Kim JE,Lee JY,et al.Increased expression of IL-18 in cutaneous graft- versus-host disease[J]. Immunol Lett,2004,95(1):57-61.
[25] Kaiser P. Turkey and chicken interleukin 18 (IL-18) share high se quence identity, but have different polyadenylation sites in their 3′UTR [J]. Dev Comp Immunol, 2002; 26 (8):681-687.
[26] Burns K, Martinon F, Esslinger C, et al. MyD88, an adapter protein involved in interleukin-1 signaling [J]. J Biol Chem, 1998, 273 (20) : 12203-12209.
[27]Andre R, Wheeler RD, Collins PD, et al. Identification of a truncated IL-18R beta mRNA: a putative regulator of IL-18 expressed in rat brain[J]. J N euroimm unol, 2003, 145 (122):40-45.
[28] Kohno K, Kataoka J, Ohtsuki T, et al. IFN-γ-inducing factor ( IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12 [J]. J Immunol, 1997, 158: 1541-1550.
[29] Micallef MJ, Ohtauki T, Kohno K, et al. Interferon-γ inducing factor enhances T helper 1 cytokine production by stimulated human T cell: synergism with interleukin-12 for interferon-γ production[J]. Eur J Immunol, 1996, 26: 1647-1651.
[30] Naumnik W, Chyczewska E, Kovalchuk O, et al. Serum levels of interleukin-18 ( IL-18) and soluble interleukin-2 receptor ( sIL-2R) in lung cancer[J]. Rocz Akad Med Bialymst, 2004, 49: 246 -251.
[31] Hata H, Yoshimoto T, Hayashi N, et al.IL-18 togather with anti-CD3 antibody induces humans Th1 cells to produce Th1- and Th2-cytokines and IL-8[J].Int Immunol,2004,16 (2):1733- 1739.
[32] Takeda K, Tsutsui H, Yoshimoto T, et al. Defective NK cell activity and Th1 response in IL-18- deficient mice [J]. Immunity, 1998, 8: 383 - 390. [33 ] Okano F, Yamada K. Canine interleukin-18 induced apop tosis and enhances Fas ligand mRNA exp- ression in a canine carcinoma cell line[J]. Anticancer Res, 2000, 20: 3411-3416.
[34] Tomura M, Zhou XY, Maruo S, et al. A critical role for IL-18 in the proliferation and activation of NK1,1+CD3 cells. J Immunol,1998,160(10):4738- 4736.
[35] Shin HD, Kim LH, Park BL, et al. Association of interleukin 18 (IL18) polymorphisms with specific IgE levels to mite allergens among asthmatic patients[J]. Allergy,2005,60(7):900-906.
[36] Jin M, Jung HJ, Choi JJ, et al. Activation of seclective transcription factors and cytokines by water-souble extract from lentinus lepideus[J].Exp Biol Med(Maywood),2003, 228(6):749-758.
[37] Reddy P. Interleukin-18: recent advances[J]. Curr Opin Hematol,2004,11(6):405- 410.
[38] Yoshimoto T and Nakanishi K. Roles of IL-18 in Basophils and Mast Cells[J]. AllergologyInternational, 2006,55:105-113.
[39] Cao R,Famebo J, Kurimoto M, et al.Interleukin-18 acts as an angiogenesis and tumor suppressor[J]. FASEB J, 1999,13(15):2195-2202.
[40] Kikuchi T, Akasaki Y, Joki T, et al. Antitumor activity of IL-18 on mouse glioma cells[J].J Immunother, 2000,23(2):184-189.
[41] Coughlin CM, Salhany KE, Wysocka M, et al.Interleukin-12 and Interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis[J]. J Clin Invest, 1998,101(6):1441- 1452.
[42] Park CC, Morel JC, Amin MA,et al.Evidence of IL-18 as a novel angiogenic medistor[J].J Immunol, 2001, 167(3):1644-1653.
[43] Kohka H,Yoshino T,Iwagaki H,et al.Interleukin-18/Interferon-gamma-ingucing factor,a novel cytokine, up-regulates ICAM-1(CD54)expression in KG-1 cells[J].J Leukoc Biol,1998,64(6):519-527.
[44] Vidal-Vanachocha F, Fantuzzi G, Mendoza L, et al.IL-18 regulates IL-1beta-dependent hepatic melanoma metastsis via vascular cell adhension molecule-1[J].Proc Natl Acad Sci USA,2000,97(2): 734-739.
[45] 钟慈声,孙安阳. 一氧化氮的生物医学[M]. 上海:上海医科大学出版社,1997 ,3 -391.
[46] Nathan C, Xie QW.Nitric oxide synthase:roles,tolls and controls.Cell,1994,78:915-918.
[47] Alderton WK,Cooper CE,Knowles RG.Nitric oxide synthase:stucture, function and inhibition[J]. Biochem J,2001,357:593-615.
[48] Sen R,Baltimore D.Mufiple nuclear fators interact with the immunoglobulin enhancer sequences[J]. Cell, 1986,46:705- 710. [49 ] Roland MS, Guido A. NF-κB /Rel/ IκB: Implications in gastrointestinal diseases[J]. Gastroentero, 2000, 118 (6) : 1208.
[50] Eric G L, David L B, Sophia C, et al. Failure to regulate TNF-induced NF-κB and cell death responses in A20deficient mice [J]. Scie, 2000, 289 (5488) : 2350.
[51] Shinichi K, Masashi S, Futoshi T, et al. Evidence that de novo protein synthesis is dispensable for antiapoptotic effects of NF-κB [J]. Oncogene, 2000, 19, (17) : 2233.
[52] Rodney WK, Anne EK and Hiary OD. Cytokine control in human endometrium[J]. Reproduction, 2001,121: 3-19.
[53] Nair A, Venkatraman M,Malieka TT, et al. NF-κB is constitutive activated in high-grade squamous intraepithelia llesions and squamous cell carcinmas of the human uterine cervix[J]. Oncogene ,2003,22: 50-58.
[54] Aradhya S, Nelson DL.NF-kappaB signaling and human disease[J]. Curr Opin Genet Dev,2001,11(3): 300- 306.
[55] Vandenbroeck K, Alloza I ,Gadina M , et al . Inhibiting cytokines of the interleukin-12 family : recent advances and novel challenges[J] . J Pharmacol ,2004 ,56 (2) :145-160.
[56] Li-weber M , Giaisi M , Baumann S , et al . NF-Kappa B Synergizes wit h NF-AT and NF-IL-6 in activation of the IL-4 gene in T-cell [J] . Eur J Immunol , 2004 ,34 (4) :1111- 1118.
[57] Das J, Chen CH, Yang L, et al . A critical role for NF-kappa B in GATA-3 expression and Th2 differentiation in allergic airway inflammation[J] . Nat Immunol ,2001 ,2 (1) :45-50.
[58] Hilliard BA, Mason N, Xu L, et al . Critical roles of C-Rel in autoimmune inflammation and helper Tcell differentiation [J] . J Clin I nvest ,2002 ,110 :843-850.
[59] Artis D, Shapira S, Mason N , et al . Differential requirement for NF-kappa B family members in cont rol of helmint h infection and intestinal inflammation[J] . J Immunol , 2002 ,169 : 4481-4487.
[60] Liou HC , Hsia CY. Distinctions between c-Rel and ot her NF-kappa B proteins in immunity and disease[J] . Bioessays , 2003 ,25 :767-780.
[61] Pai SY, Ho IC. C-Rel delivers a one-two punch in Th1 cell differentiation[J] . J Clin I nvest , 2002 , 110 : 741-742.
[62] Sha WC, Liou HC, Tuomanen EI, et al. Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses[J]. Cell, 1995, 80:321-330.
[63] Yoshimura S, Bondeson J, Brennan FM, et al. Role of NF-κB in antigen presentation and development of regulatory T cells elucidated by treatment of dendritic cells with the proteasome inhibitor PSI [J]. Eur J Immunol, 2001, 31:1883-1889.
[64] Marurno T, Schini-Kerth VB, Busse R.Vascular endothelial growth factor activates nuclear factor- kappaB and induces monocyte chemottractant protein-1 in bovine retinal endothelial cells[J].Diabetes, 1999,48(5): 1131-1138.
[65]Taniguchi M,Nagaoka K, Kunikata T, et al. Characterization of anti human interleukin-18(IL-18)/ interferon-gamma inducing factor(IGIF) monoclonal antibodies and their application in the measurement of human IL-18 by ELISA[J]. J Immonol Methods,1997,206 (1-2):107-113.
[66]Xu D, Chan WL, Leung PP, et al. Selective expression and functions of interleukin 18 receptor T helper (Th ) type 1 but not Th2 cells[J].J Exp Med,1998,188(8):1485-1492.
[67] Guilbert L. There is a bias against type 1 inflammatory cytokine expression and function in pregnancy [J]. J Reprod Immunol,1998,39:362-367.
[68] Ledee-Bataille N, Olivennes F, Kadoch J, et al. Detectable levels of interleukin-18 in uterine luminal secretions at oocyte retrieval predict failure of the embryo transfer[J]. Hum Reprod, 2004, 19(9):1968- 1973.
[69] Herington JL, Bany BM. Effect of the conceptus on uterine natural killer cell numbers and function in the mouse uterus during decidualization[J].Biol Reprod,2007 ,76(4):579-588.
[70] Laskarin G, Strbo N, Bogovic Crncic T, et al. Physiological role of IL-15 and IL-18 at the maternal- fetal interface[J]. Chem Immunol Allergy. 2005,89:10- 25.
[71] Tokmadzic VS, Tsuji Y, Bogovic T, et al. IL-18 is present at the maternal-fetal interface and enhances cytotoxic activity of decidual lymphocytes[J]. Am J Reprod Immunol,2002,48(4): 191- 200.
[72] Xie X, He H, Colonna M, et al. Pathways participating in activation of mouse uterine natural killer cells during pregnancy[J]. Biol Reprod,2005 ,73(3):510-518.
[73] Lédée N, Dubanchet S, Lombroso R, et al. Downregulation of human endometrial IL-18 by exogenous ovarian steroids[J].Am J Reprod Immunol, 2006,56(2):119-123.
[74] Sakai M, Shiozaki A, Sasaki Y, et al.The ratio of interleukin (IL)-18 to IL-12 secreted by peripheral blood mononuclear cells is increased in normal pregnant subjects and decreased in pre-eclamptic patients[J]. J Reprod Immunol,2004,61(2):133-143.
[75] 王春,尚涛.IL-18与妊娠、分娩关系的研究[J].中华临床医药,2002,3(23): 27-28.
[76] Ida A, Tsuji Y, Muranaka J, et al. IL-18 in pregnancy: the elevation of IL-18 in maternal peripheral blood during labour and complicated pregnancies[J]. J Reprod Immunol, 2000,47(1):65-74.
[77] Mansouri R, Akbari F, Vodjgani M, et al..Serum cytokines profiles in Iranian patients with preeclampsia[J]. Iran J Immunol. 2007 ,4(3):179-185.
[78] Huang XD, Huang HF, Dong MY, et al. Relationship between serum and placental interleukin-18 levels and preeclampsia[J].Zhejiang Da Xue Xue Bao Yi Xue Ban,2005,34(6): 495-498.
[79] Wang X, Hagberg H, Mallard C, et al. Disruption of interleukin-18, but not interleukin-1, increases vulnerability to preterm delivery and fetal mortality after intrauterine inflammation[J].Am J Pathol ,2006,169(3):967-976.
[80] Wilson R, Jenkins C, Miller H, et al. Abnormal cytokine levels in non-pregnant women with a history of recurrent miscarriage[J]. Eur J Obstet Gynecol Reprod Biol, 2004,115(1):51-54.
[81] Tesfaye D, Kadanga A, Rings F, et al. The effect of nitric oxide inhibition and temporal expression patterns of the mRNA and protein products of nitric oxide synthase genes during in vitro development of bovine pre-implantation embryos[J]. Reprod Domest Anim, 2006 ,41(6):501-509.
[82] Zhang X, Lin HY, Liu GY, et al. Expressions and regulation of endothelial and inducible nitric oxide synthases in mouse uterus during the estrous cycle and early pregnancy[J]. Front Biosci, 2005,10(9): 3172-3182.
[83] Okawa T, Asano K, Takahashi H, et al. Expression of inducible nitric oxide synthase messenger RNA, but not guanylate cyclase messenger RNA, depends on gestational age in rat myometrium[J]. Gynecol Endocrinol, 2004,19(3): 146-151.
[84] Vaisanen-Tommiska M, Butzow R, et al. Mifepristone-induced nitric oxide release and expression of nitric oxide synthases in the human cervix during early pregnancy[J]. Hum Reprod.,2006 21(8): 2180-2184.
[85] Aalberts M, van Dissel-Emiliani FM, van Tol HT, et al. High iNOS mRNA and protein levels during early third trimester suggest a role for NO in prelabor cervical ripening in the bovine[J]. Mol Reprod Dev, 2007 , 4(3):378-385.
[86] 王山米,许艳,虞有智.妊娠晚期和分娩期诱导型一氧化氮合酶在子宫下段及胎盘的定位与活性观察[J].中国实用妇科与产科杂志,2002,18(11):670-672.
[87] 王俊梅,宋明清,刘斌.诱生型一氧化氮合酶抑制剂氨基胍对鼠胚发育的影响[J].北京大学学报( 医学版), 2001,33(2):153-156.
[88] Cella M, Aisemberg J, Sordelli MS, et al. Prostaglandins modulate nitric oxide synthase activity early in time in the uterus of estrogenized rat challenged with lipopolysaccharide[J]. Eur J Pharmacol, 2006 ,534(1-3):218-226.
[89] 张育新,潘维梅,赵春丽.一氧化氮在妊高征发病机理中的作用[J].齐齐哈尔医学院学报,2001,22(7):755-757.
[90] 林晓娟,严亚迎,高英敏.诱导型一氧化氮合酶和P 选择素在早期自然流产中的表达及临床意义[J].生殖医学,中国生育健康杂志,2004,15(2):92-95.
[91] Tornblom SA, Maul H, Klimaviciute A,et al.mRNA expression and localization of bNOS, eNOS and iNOS in human cervix at preterm and term labour[J]. Reprod Biol Endocrinol,2005, 10(3):33.
[92] Schiessl B, Mylonas I, Hantschmann P,et al. Expression of endothelial NO synthase, inducible NO synthase, and estrogen receptors alpha and beta in placental tissue of normal, preeclamptic, and intrauterine growth-restricted pregnancies[J]. J Histochem Cytochem., 2005 ,53(12):1441-1449.
[93] 谢青贞,辛志敏.核因子-κB与生殖调节[J].国外医学妇产科学分册,2002,29(4):223-225.
[94] Nakamura H, Kimura T, Ogita K, et al. Alteration of the timing of implantation by in vivo gene transfer: delay of implantation by suppression of nuclear factor kappaB activity and partial rescue by leukemia inhibitory factor[J].Biochem Biophys Res Commun,2004, 321 (4):886-892.
[95] Muggia A, Teesalu T, Neri A, et al. Trophoblast giant cells express NF- kappaB2 during early mouse development[J] . Dev Ge-net ,1999,25:23-30.
[96] Allport VC, Pieber D, Slater DM, et al. Human labour is associated with nuclear factor kappaB activity uhich mediates cyclooxygenase-2 expression and is involved with the ’functional prgesterone withdrawal’ [J]. Mol Hum Reprod , 2001 ,7 :581-586.
[97] Goebeler M, Gillitzer R , Kilian K, et al. Multiple sigaling pathways regulate NF-kappa B-dependent transcription of the monocyte chemoattractant protein -1 gene in primary endothelial cells [J ] . Blood , 2001 , 97(1) :46-55.
[98] 曲鑫,张树泉,姜学强,等.核因子κB及黏附分子在妊娠高血压综合征患者胎盘组织中的表达[J]. 中华妇产科杂志2005,40(10):701-703.
[99] Schmitz T, Souil E, Hervé R, et al. PDE4 inhibition prevents preterm delivery induced by an intrauterine inflammation[J ].J Immunol, 2007, 178(2):1115- 1121.
[100] Shah TJ, Walsh SW. Activation of NF-kappaB and expression of COX-2 in association with neutrophil infiltration in systemic vascular tissue of women with preeclampsia[J]. Am J Obstet Gynecol, 2007 ,196 (1):48:1-8.
[101] 张宁,徐永健,张珍祥,等.一氧化氮-核因子-κB信号通路在支气管哮喘患者T细胞功能表达中的作用[J].中华内科杂志,2005,44(5):328-332.
[102] 张宁.一氧化氮对核因子-κB的反馈调节作用[J].国外医学呼吸系统分册,2002,22 (2):66- 69.
[103] Andre R, Wheeler RD, Collins PD, et al. Identification of a truncated IL-18R beta mRNA: a putative regulator of IL-18 expressed in rat brain[J]. J Neuroimmunol,2003,145(1-2):40-45
[104] Culhane AC, Hall MD, Rothwell NJ, et al. Cloning of rat brain interleukin-18 cDNA[J]. Mol Psychiatry, 1998 ,3(4):362-366.
[105] Wang N, Sugama S, Conti B, et al. Interleukin-18 mRNA expression in the rat pituitary gland[J]. J Neuroimmunol, 2006,173(1-2):117-125.
[106] Nagai Y, Nochi T, Watanabe K, et al. Localization of interleukin-18 and its receptor in somatotrophs of the bovine anterior pituitary gland[J]. Cell Tissue Res, 2005,322(3):455- 462.
[107] Nagai Y, Watanabe K, Aso H, et al. Cellular localization of IL-18 and IL-18 receptor in pig anterior pituitary gland[J]. Domest Anim Endocrinol, 2006,30(2):144-154.
[108] Tsuji Y, Tamaoki TH, Hasegawa A, et al. Expression of interleukin-18 and its receptor in mouse ovary[J]. Am J Reprod Immunol, 2001,46(5):349-357.
[109] Gutman G, Soussan-Gutman L, Malcov M, et al. Interleukin-18 is high in the serum of IVF pregnancies with ovarian hyperstimulation syndrome[J]. Am J Reprod Immunol, 2004 ,51(5): 381- 394.
[110] Murakami Y, Otsuki M, Kusumoto K, et al. Estrogen inhibits interleukin-18 mRNA expression in the mouse uterus[J]. J Reprod Dev, 2005,51(5):639-647.
[111] Ida A, Tsuji Y, Muranaka J, et al. IL-18 in pregnancy; the elevation of IL-18 in maternal peripheral blood during labour and complicated pregnancies[J]. J Reprod Immunol, 2000 May;47(1):65-74.
[112] 胡昌东,归绥琪.自然流产患者滋养细胞肝素表皮生长因子的表达和意义[J].上海医学,2004,27(7):491- 494.
[113] 吴浩,常雅萍,于永利.Th1 型/Th2 型细胞因子与妊娠的免疫调节[J].国外医学.免疫学分册,1999:22(2):57-66.
[114] Culhane AC, HallMD, RothwellNJ, et al. Cloning of rat brain interleukin-18 cDNA[J]. Mol Psychiatry, 1998, 3 (4) : 362-366.
[115]Sugama, S,Cho BP, Baker H, et al. Neurons of the superior nucleus of the medial habenula and ependymal cells express IL-18 in rat CNS[J]. Brain Res, 2002,958(1):1–9.
[116]Andre R, Wheeler RD, Collins PD, et al. Identification of a truncated IL-18R beta mRNA: a putative regulator of IL-18 expressed in rat brain[J]. J Neuroimmunol,2003 ,145(1-2):40-55.
[117] Sugama S, Fujita M, Hashimoto M, et al. Stress induced morphological microglial activation in the rodent brain: involvement of interleukin-18[J]. Neuroscience , 2007, 146(3): 1388-1399.
[118] Koibuchi N , Fujita M , Hashimoto M , et al. The adrenal gland is a source of stress-induced circulating IL-18[J].Journal of Neuroimmunology, 2006,172:59-65.
[119] Wang N, Sugama S, Conti B, et al. Interleukin-18 mRNA expression in the rat pituitary gland[J]. J Neuroimmunol ,2006 ,173(1-2):117-125.
[120] Igaz P, Salvi R, Rey JP, et al.Effects of Cytokines on Gonadotropin- Releasing Hormone (GnRH) Gene Expression in Primary Hypothalamic Neurons and in GnRH Neurons Immortalized Conditionally[J]. Endocrinology , 2006,147(2):1037-1043.
[121]Yamaguchi M, Koike K, Yoshimoto Y, et al. Interleukin-6 stimulates gonadotropin- releasing hormone secretion from rat hypothalamic cells[J]. Horm Res,1991,35:252-256
[122] Yamaguchi M, Yoshimoto Y, Komura H, et al. Interleukin 1β and tumour necrosis factor αstimulate the release of gonadotropin-releasing hormone and interleukin 6 by primary cultured rat hypothalamic cells[J]. Acta Endocrinol (Copenh), 1990,123:476-480.
[123] Kang SS, Kim SR, Leonhardt S, et al. Effect of interleukin-1βon gonadotropin- releasing hormone (GnRH) and GnRH receptor gene expression in castrated male rats[J]. J Neuroendocrinol, 2000,12: 421- 429.
[124] Feleder C, Arias P, Refojo D, et al. Interleukin-1 inhibits NMDA-stimulated GnRH secretion: associated effects on the release of hypothalamic inhibitory amino acid neurotransmitters[J]. Neuroimmuno- modulation,2000, 7:46-50.
[125]Kanno T, Nagata T, Yamamoto S, et al. Interleukin-18 stimulates synaptically released glutamate and enhances postsynaptic AMPA receptor responses in the CA1 region of mouse hippocampal slices[J]. Brain Res ,2004,1012(1-2):190-193.
[126] Schneider, E. Pro-Th1 cytokines promote Fas-dependent apoptosis of immature peripheral basophils[J]. J Immunol,2004,172:5262-5268.
[127] Chandrasekar, B. Activation of intrinsic and extrinsic pro-apoptotic signaling pathways in interleukin-18-mediated human cardiac endothelial cell death[J]. J Biol. Chem, 2004,279:20221- 20233.
[128] Finotto, S. Severe hepatic injury in interleukin-18 (IL-18) transgenic mice: a key role for IL-18 in regulating hepatocyte apoptosis in vivo[J]. Gut ,2004 , 53:392-400.
[129] Bushley AW,Ferrell R,Mcduffie K,et al.Polymorphisms of interleukin(IL)-1alpha, IL-1beta, IL-6,IL-10 and IL-18 and the risk of ovarian cancer[J]. Gynecol Oncol,2004,95(3):672-679.
[130] Pitzel L, Jarry H and Wuttke W. Effects and interactions of prostaglandin , oxytocin and cytokines on steroidogenesis of porcine luteal cells[J]. The Endocrine Society ,1993,132 (2 ): 751-756.
[131] Vujisic S, Lepej SZ, Emedi I, et al. Ovarian follicular concentration of IL-12, IL-15, IL-18 and p40 subunit of IL-12 and IL-23 [J]. Hum Reprod, 2006 , 21 (10):2650-2655.
[132] Huck B, Steck T, Habersack M, et al. Pregnancy associated hormones modulate the cytokine production but not the phenotype of PBMC- derived human dendritic cells[J]. Eur J Obstet Gynecol Reprod Biol, 2005,122(1):85-94.
[133] Lédée N, Dubanchet S, Lombroso R, et al. Downregulation of human endometrial IL-18 by exogenous ovarian steroids. Am J Reprod Immunol, 2006 ,56(2):119-123.
[134] Ledee-Bataille N, Dubanchet S, Coulomb-L'hermine A, et al.A new role for natural killer cells, interleukin (IL)-12, and IL-18 in repeated implantation failure after in vitro fertilization [J]. Fertility and Sterility,2004,81(1): 59-65.
[135] Luo Q, Ning WX, Wu YT, et al.Altered expression of interleukin-18 in the ectopic and eutopic endometrium of women with endometriosis [J]. Journal of Reproductive Immunology,2006,72 (1-2):108-117.
[136] Zhang JH, He H, Borzychowski AM., et al. Analysis of Cytokine Regulators Inducing Interferon Production by Mouse Uterine Natural Killer Cells [J]. Biology of Reproduction, 2003,69(2):404-411.
[137] Chaouat G, Zourbas S, Ostojic S, et al. A brief review of recent data on some cytokine expressions at the materno-foetal interface which might challenge the classical Th1/Th2 dichotomy[J] . Journal of Reproductive Immunology, 2002, 53(1-2): 241-256.
[138] Rivier C. Role of gaseous neurotransmitters in the hypothalamic-pituitary- adrenal axis[J]. Ann N Y Acad Sci, 2001,933:254-264.
[139] Wood CE, Giroux D. Expression of nitric oxide synthase isoforms in the ovine fetal brain: alteration by hormonal and hemodynamic stimuli[J]. J Soc Gynecol Investig, 2006 ,13(5): 329-337.
[140] Akasaka S, Nomura M, Nishii H, et al. The hypothalamo-pituitary axis responses to lipopolysaccharide-induced endotoxemia in mice lacking inducible nitric oxide synthase[J]. Brain Res, 2006,1089(1):1-9.
[141] Ca?ka J. The role of nitric oxide in the hypothalamic control of LHRH and oxytocin release, sexual behavior and aging of the LHRH and oxytocin neurons[J]. Folia Histochem Cytobiol. 2006;44(1): 3-12.
[142] Grange-Messent V, Raison D, Dugas B, et al. Noradrenaline up-regulates the neuronal and the inducible nitric oxide synthase isoforms in magnocellular neurons of rat brain slices[J]. Calas A. J Neurosci Res, 2004 ,78(5):683-690.
[143] Kjeldsen TH, Rivier C, Lee S, et al.Inducible nitric oxide synthase is responsible for nitric oxide release from murine pituicytes[J]. J Neuroendocrinol, 2003 ,15(3): 250-255.
[144] Mccann SM, Kimura M, Karanth S, et al.The Mechanism of Action of Cytokines to Control the Release of Hypothalamic and Pituitary Hormones in Infection[J] . Annals of the New York Academy of Sciences, 2000,917:4-18.
[145] Uretsky AD, Weiss BL, Yunker WK, et al.Nitric oxide produced by a novel nitric oxide synthase isoform is necessary for gonadotropin-releasing hormone- induced growth hormone secretion via a cGMP- dependent mechanism[J]. J Neuroendocrinol, 2003,15(7):667-676.
[146] Kim H, Moon C, Ahn M, et al. Expression of nitric oxide synthase isoforms in the porcine ovary during follicular development. J Vet Sci[J], 2005,6(2):97-101.
[147] Matsumi H, Yano T, Osuga Y, et al. Regulation of nitric oxide synthase to promote cytostasis in ovarian follicular development[J]. Biol Reprod, 2000 ,63(1):141-146.
[148] Mitchell LM, Kennedy CR, Hartshorne GM. Expression of nitric oxide synthase and effect of substrate manipulation of the nitric oxide pathway in mouse ovarian follicles[J]. Hum Reprod, 2004,19(1):30-40.
[149] Chen Q, Yano T, Matsumi H, et al. Cross-Talk between Fas/Fas ligand system and nitric oxide in the pathway subserving granulosa cell apoptosis: a possible regulatory mechanism for ovarian follicle atresia[J]. Endocrinology, 2005,146(2):808-815.
[150] Gay-Andrieu F, Cozon GJ, Ferrandiz J, et al. Progesterone fails to modulate Toxoplasma gondii replication in the RAW 264.7 murine macrophage cell line[J]. Parasite Immunol. 2002,24(4): 173-178.
[151] Rosiansky-Sultan M, Klipper E, Spanel-Borowski K, et al. Inverse relationship between nitric oxide synthases and endothelin-1 synthesis in bovine corpus luteum: interactions at the level of luteal endothelial cell[J]. Endocrinology, 2006,147(11):5228-5235.
[152] Boiti C, Zampini D, Guelfi G, et al. Expression patterns of endothelial and inducible nitric oxide synthase isoforms in corpora lutea of pseudopregnant rabbits at different luteal stages [J]. J Endocrinol, 2002,173 (2):285-296.
[153] Hurwitz A, Finci-Yeheskel Z, Milwidsky A, et al. Regulation of cyclooxygenase activity and progesterone production in the rat corpus luteum by inducible nitric oxide synthase[J]. Reproduction, 2002,123(5):663-669.
[154] Tobai H, Nishiya I. Nitric oxide mediates inhibitory effect of interleukin-1beta on estrogen production in human granulosa-luteal cells[J]. J Obstet Gynaecol Res, 2001 ,27(1):53-59.
[155] Gay-Andrieu F, Cozon GJ, Ferrandiz J, et al. Progesterone fails to modulate Toxoplasma gondii replication in the RAW 264.7 murine macrophage cell line[J]. Parasite Immunol, 2002 ,24(4): 173-178.
[156] Yang H, Bhat GK, Wadley R, et al. Gonadotropin-releasing hormone-agonist inhibits synthesis of nitric oxide and steroidogenesis by luteal cells in the pregnant rat[J]. Biol Reprod, 2003,68(6): 2222-2231.
[157] Zhang X, Lin HY, Liu GY, et al. Expressions and regulation of endothelial and inducible nitric oxide synthases in mouse uterus during the estrous cycle and early pregnancy[J]. Front Biosci, 2005,10: 3172- 3182.
[158] Welter H, Bollwein H, Weber F, et al. Expression of endothelial and inducible nitric oxide synthases is modulated in the endometrium of cyclic and early pregnant mares[J]. Reprod Fertil Dev, 2004,16(7): 689-698.
[159] Burnett TG, Hunt JS. Nitric oxide synthase-2 and expression of perforin in uterine NK cells [J]. J Immunol, 2000 ,164(10):5245-5250.
[160] Okada Y, Asahina T, Kobayashi T, et al. Studies on the mechanism of edematous changes at the endometrial stroma for implantation[J]. J Immunol, 2001;27(2):67-77..
[161] Burnett TG, Tash JS, Hunt JS. Investigation of the role of nitric oxide synthase in pregnancy usingmutant mice[J]. Reproduction. 2002,124(1):49-57.
[162] Kwon H, Wu G, Meininger CJ, et al. Developmental changes in nitric oxide synthesis in the ovine placenta[J]. Biol Reprod, 2004 ,70(3):679-686.
[163] Farina M, Ribeiro ML, Franchi A. Nitric oxide synthases in pregnant rat uterus[J]. Reproduction, 2001, 121(3):403-407.
[164] Yallampalli C, Dong YL. Estradiol-17beta inhibits nitric oxide synthase (NOS)-II and stimulates NOS-III gene expression in the rat uterus[J]. Biol Reprod, 2000,63(1):34-41.
[165]Mccracken SA, Gallery E, Morris JM.Pregnancy-specific down-regulation of NF-kappa B expression in T cells in humans is essential for the maintenance of the cytokine profile required for pregnancy success[J]. J Immunol,2004,172(7):4583-4591.
[166] Gonzalez-Navarrete F, Eisner V, Morales P, et al. Tumor necrosis factor-alpha activates nuclear factor- kappaB but does not regulate progesterone production in cultured human granulosa luteal cells[J]. Gynecol Endocrinol, 2007,23(7):377-384.
[167] Diamanti-Kandarakis E, Piperi C, Patsouris E, et al. Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries[J]. Histochem Cell Biol, 2007,127(6):581-589.
[168] Chu S, Nishi Y, Yanase T, et al. Transrepression of estrogen receptor beta signaling by nuclear factor- kappab in ovarian granulosa cells[J]. Mol Endocrinol, 2004 ,18(8):1919- 1928.
[169] Valdez KE, Turzillo AM. Regulation of nuclear factor-kappaB (NF-kappaB) activity and apoptosis by estradiol in bovine granulosa cells[J]. Mol Cell Endocrinol, 2005 ,243(1-2):66- 73.
[170] Kelly RW, King AE, Critchley HO. Cytokine control in human endometrium[J]. Reproduction, 2001,121(1):3-19.
[171] Son DS, Roby KF. Interleukin- 1alpha-induced chemokines in mouse granulosa cells: impact on keratinocyte chemoattractant chemokine, a CXC subfamily[J]. Mol Endocrinol. 2006,20(11):2999- 3013.
[172] Xiao CW, Asselin E, Tsang BK. Nuclear factor kappaB-mediated induction of Flice-like inhibitory protein prevents tumor necrosis factor alpha-induced apoptosis in rat granulosa cells[J]. Biol Reprod, 2002 ,67(2):436-441.
[173] Telleria CM, Goyeneche AA, Stocco CO, et al. Involvement of nuclear factor kappa B in the regulation of rat luteal function: potential roles as survival factor and inhibitor of 20 alpha-hydroxysteroid dehydrogenase[J]. J Mol Endocrinol, 2004 ,32(2):365-383.
[174] Martin R D , Hoeth M , Hofer-Warbinek R. The Transcription Factor NF-kB and the Regulation of Vascular Cell Function[J]. Arterioscler Thromb Vasc Biol,2000,20(11): 83- 88.
[175] van der Burg B, van der Saag PT. Nuclear factor-kappa-B/steroid hormone receptor interactions as a functional basis of anti-inflammatory action of steroids in reproductive organs[J]. Mol Hum Reprod, 1996,2(6):433-438.
[176] Xie Q, Xin Z, Cao L, et al. Expression of nuclear factor-kappaB in mouse uterus during peri-implantation [J]. J Huazhong Univ Sci Technolog Med Sci, 2004,24(4):361-364.
[177] Geisert RD, Ross JW, Ashworth MD, et al. Maternal recognition of pregnancy signal or endocrine disruptor: the two faces of oestrogen during establishment of pregnancy in the pig[J]. Endocrinology, 2007,148: 4761-4773.
[178] King AE, Critchley HO, Kelly RW. The NF-kappaB pathway in human endometrium and first trimester decidua[J]. Mol Hum Reprod, 2001,7(2):175-183.
[179] Nakamura H, Kimura T, Ogita K, et al.NF-kappaB activation at implantation window of the mouse uterus[J]. Am J Reprod Immunol, 2004 ,51(1):16-21.
[180] Mccracken SA, Hadfield K, Rahimi Z, et al. NF-kappaB-regulated suppression of T-bet in T cells represses Th1 immune responses in pregnancy[J]. Eur J Immunol. 2007 May;37(5): 1386-1396.
[181] Mccracken SA, Gallery E, Morris JM. Pregnancy-specific down-regulation of NF-kappa B expression in T cells in humans is essential for the maintenance of the cytokine profile required for pregnancy success [J]. J Immunol, 2004,172(7):4583-4591.
[182] Lappas M, Permezel M, Holdsworth SJ, et al. Antiinflammatory effects of the cyclopentenone isoprostane 15-A(2)-IsoP in human gestational tissues[J]. Free Radic Biol Med, 2007,42(12): 1791-1796.
[183] Mendelson CR, Condon JC. New insights into the molecular endocrinology of parturition[J]. J Steroid Biochem Mol Biol, 2005,93(2-5):113-119.
[184] Shimizu S, Tahara M, Ogata S, et al. Involvement of nuclear factor-kB activation through RhoA/ Rho- kinase pathway in LPS-induced IL-8 production in human cervical stromal cells [J]. Mol Hum Reprod, 2007,13(3):181-187.
[185] Condon JC, Hardy DB, Kovaric K, et al. Up-regulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear factor-kappaB may contribute to the onset of labor through inhibition of PR function. Mol Endocrinol[J]. 2006 ,20(4):764- 775.
[186] Dosiou C, Giudice LC. Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives[J]. Endocrine,2000,26(1):44-62.
[187] 唐薇.米非司酮终止妊娠的分子免疫机制[J].海南医学,2005,16(3):124-126.
[188] Gruber CJ, Huber JC. The role of dydrogesterone in recurrent abortion[J]. J Steroid Biochen Mol Biol, 2005,97 (5):426-430.
[189] Ostoji? S, Volk M, Medica I,et al. Polymorphisms in the interleukin-12/18 genes and recurrent spontaneous abortion[J]. Am J Reprod Immunol. 2007 ,58(5):403-408.
[190] Mansouri R, Akbari F, Vodjgani M,et al.Serum cytokines profiles in Iranian patients with preeclampsia [J]. 2007 ,4(3):179-185.
[191] Gracie JA, Robertson SE, McInnes IB. Interleukin-18[J]. J Leukoc Biol, 2003,73:213–224.
[192] Andrea R, Wheelerb RD, Collinsa PD, et al. Identification of a truncated IL-18Rh mRNA: a putative regulator of IL-18 expressed in rat brain[J]. Journal of Neuroimmunology , 2003, 145:40–45.
[193] Felderhoff-Mueser U ,Schmidt OI, Oberholzer A, et al. IL-18: a key player in neuroinflammation and neurodegeneration[J].Trends in Neurosciences, 2005,28(9):487- 493.
[194] Kanno, T. Interleukin-18 stimulates synaptically released glutamate and enhances postsynaptic AMPA receptor responses in the CA1 region of mouse hippocampal slices[J]. Brain Res, 2004,1012:190–193.
[195] Zhang YF, Yang YS, Hong J, et al. Elevated serum levels of interleukin-18 are associated with insulin resistance in women with polycystic ovary syndrome[J]. Endocrine, 2006 ,29(3):419-423.
[196]Sarkar NN. The potential of mifepristone (RU486) as a female contraceptive drug[J]. Int J Clin Pract , 2002 , 56 (2) :140-144.
[197] Naeimi S, Ghiam A F, Mojtahedi Z, et al. Interleukin-18 gene promoter polymorphisms and recurrent spontaneous abortion[J]. Eur J Obstet Gynecol Reprod Biol, 2006,128(1-2): 5- 9.
[198] Zicari A, Ticconi C, Ietta F, et al. Macrophage migration inhibitory factor-nitric oxide interaction in human fetal membranes at term pregnancy[J]. J Soc Gynecol Investig ,2006 , 13(4):263-270.
[199] Wang C, Hikim AS, Ferrini M, et al. Male reproductive ageing: using the brown Norway rat as a model for man[J]. Novartis Found Symp,2002,242:82-95.
[200] Gonzalez-Cadavid NF, Swerdloff RS, Ferrini M, et al. Aging-related increased expression of inducible nitric oxide synthase and cytotoxicity markers in rat hypothalamic regions associated with male reproductive function[J]. Neuroendocrinology,2001,74(1):1-11. [ 201] Dingman A, Lee SY, Derugin N, et al. Aminoguanidine inhibits caspase-3 and calpain activation without affecting microglial activation following neonatal transient cerebral ischemia[J]. J Neurochem,2006, 96(5):1467-1479.
[202] Neuvians TP, Schams D, Berisha B, et al. Involvement of pro-inflammatory cytokines, mediators of inflammation, and basic fibroblast growth factor in prostaglandin F-alpha-induced luteolysis in bovine corpus luteum[J]. Biol Reprod,2004, ,70(2):473-480.
[203] Mitchell LM, Kennedy CR, Hartshorne GM.Expression of nitric oxide synthase and effect of substrate manipulation of the nitric oxide pathway in mouse ovarian follicles[J]. Hum Reprod, 2004 ,19(1):30-40.
[204] Sundaresan NR, Saxena VK, Sastry KV, et al. Nitric oxide: a possible mediator of ovulation and postovulatory follicle regression in chicken[J]. Anim Reprod Sci, 2007 ,101(3-4):351- 357.
[205] Casais M, Delgado SM, Vallcaneras S, et al. Nitric oxide in prepubertal rat ovary contribution of the ganglionic nitric oxide synthase system via superior ovarian nerve[J]. Neuro Endocrinol Lett,2007,28(1): 39-44.
[206] Okawa T, Asano K, Takahashi H, et al. Expression of inducible nitric oxide synthase messenger RNA, but not guanylate cyclase messenger RNA, depends on gestational age in rat myometrium[J]. Gynecol Endocrinol , 2004 ,19(3):146-51.
[207] Baylis SA, Strijbos PJ, Sandra A, et al. Temporal expression of inducible nitric oxide synthase in mouse and human placenta[J]. Mol Hum Reprod,1999,5(3):277-286.
[208] Zhang X, Lin HY, Liu GY, et al. Expressions and regulation of endothelial and inducible nitric oxide synthases in mouse uterus during the estrous cycle and early pregnancy[J]. Front Biosci ,2005,10: 3172- 3182.
[209]Emanuela M, Iorio D, Romolo, et al. Adrenomedullin and nitric oxide synthase at the maternal- decidual interface in early spontaneous abortion[J].Journal of Reproductive Medicine,2004, 49 (3): 153-161.
[210] Kwon H, Wu G, Meininger CJ, et al.Developmental changes in nitric oxide synthesis in the ovine placenta[J].Biol Reprod,2004, 70(3):679-686.
[211] 沈政,铁国栋,赵兴绪,等.雌性动物生殖系统中的一氧化氮[J].细胞生物学杂志, 2004,26: 349-351.
[212] Marinoni E, Di Iorio R, Villaccio B, et al.Amniotic fluid nitric oxide metabolite levels and nitric oxide synthase localization in feto-placental tissues are modified in association with human labor[J]. Eur J Obstet Gynecol Reprod Biol,2000, 89(1):47-54.
[213] Jiang RZ, Huang YJ, Gu JH, et al.Effects of nuclear factor-kappaB decoy oligodeoxynucleotide onthe function of human umbilical artery smooth muscle cells induced by umbilical sera in preeclampsia[J]. Zhonghua Fu Chan Ke Za Zhi,2007,42(2):87- 91.
[214] Martin RD, Hoeth M, Hofer-Warbinek R, et al. The Transcription Factor NF-kB and the Regulation of Vascular Cell Function[J].Arterioscler Thromb Vasc Biol,2000,20(11): 83-88.
[215] Gao GL, Liu LD, Zou XS, Chen WX. Expression of KiSS-1, matrix metalloproteinase-9, nuclear factor-kappaBp65 in ovarian tumour[J]. Zhonghua Fu Chan Ke Za Zhi,2007, 42(1): 34-38.
[216] Diamanti-Kandarakis E, Piperi C, Patsouris E, et al.Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries[J]. Histochem Cell Biol, 2007, 127(6):581-589.
[217] 郑仲谨,李磊.核转录因子κB在全身炎症反应综合征中的作用[J].免疫学杂志,2001, 17(4):314-317.
[218] Valdez KE, Turzillo AM. Regulation of nuclear factor-kappaB (NF-kappaB) activity and apoptosis by estradiol in bovine granulosa cells[J]. Mol Cell Endocrinol,2005, 243(1-2):66- 73.
[219] Li MJ, Li JJ, Zhao XB, et al. Influence of mifepristone and lilopristone on proliferation and expression of nuclear factor-kappa B of ectopic stromal cells in vitro[J]. Zhonghua Fu Chan Ke Za Zhi,2005, 40(1):21-24.
[220] Wang Y, Chan S, Tsang BK. Involvement of inhibitory nuclear factor-kappaB (NFkappaB)- independent NFkappaB activation in the gonadotropic regulation of X-linked inhibitor of apoptosis expression during ovarian follicular development in vitro[J]. Endocrinology,2002 ,143(7):2732-2740.
[221] Xiao CW, Asselin E, Tsang BK. Nuclear factor kappaB-mediated induction of Flice-like inhibitory protein prevents tumor necrosis factor alpha-induced apoptosis in rat granulosa cells[J]. Biol Reprod, 2002, 67(2):436-441.
[222] Reznikov LL, Shames BD, Barton HA , et al.Interleukin-1β deficiency results in reduced NF-kB levels in pregnant mice[J].Am J Physiol Regulatory Integrative Comp Physiol, 2000, 278:263-270. .