异位灶趋化因子TECK与其受体CCR9异常调控导致子宫内膜异位症的分子机制
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摘要
在子宫内膜异位症发病机制中,Sampson的经血逆流学说已获得普遍认可。正常情况下约有50%～90%的育龄妇女发生经血逆流,但只有6.2%～8.2%罹患EMs。因此,EMs患者可能存在浆膜免疫异常,导致难以清除逆流的内膜碎屑。已有研究证据表明,EMs患者的外周及腹腔细胞免疫功能异常调控,降低了对异位子宫内膜的免疫监视、识别和清除,将促进子宫内膜的异位种植。
在子宫内膜异位症的发生和发展过程中,多种免疫细胞被募集到腹膜腔内,特别是单核巨噬细胞、T细胞亚群;且功能发生异常改变。调节性T细胞在维持免疫耐受中发挥至关重要的调节作用,在体内被趋化因子-趋化因子受体趋化到靶器官及组织,形成有利于免疫耐受的特殊免疫微环境。由于趋化因子及其受体TECK/CCR9在EMT在位内膜及异位内膜异常表达,故可能参与EMT的发生与发展。目前已知:CCR9与TECK的相互作用激活了CD4~+T细胞多种信号通路:MAPK(Mitogen-activated protein kinase)、P13k(Phosphoinositide-3 kinase)、蛋白激酶B、GSK-3β(Glycogen synthase kinase 3β)以及转录因子NF-κB,在促进T细胞的存活和增殖以及逃避Fas介导的细胞凋亡中起重要调控作用。
EMs的发病受多种因素影响:一方面,EMs是一种雌激素依赖性疾病;另一方面,环境污染物参与EMs的发病。含碳和氯燃料所产生的二噁英(TCDD)是全球普遍存在的最严重的大气污染物,可在大气中长期稳定存在。许多研究证据表明,TCDD与EMs的发病具有相关性。TCDD的亲脂特性决定其不易从尿中排泄而在体内脂肪中长期堆积,作用机制与甾体激素类似,通过与细胞内特异受体结合形成复合物,作为转录因子调控多种蛋白质分子表达。TCDD具有抗雌激素和雌激素样双重作用特性;依据年龄、月经周期、组织和其它因素变化所致的体内雌激素水平,决定着TCDD发挥雌激素效应,或抗雌激素效应。
本研究假设是:环境污染物TCDD与体内雌激素协同作用,导致腹腔内分泌-及免疫微环境改变。因此,我们通过体外构建异位灶模型,探索17β-E_2和TCDD通过调控异位灶相关细胞趋化因子TECK的分泌,进而募集CD4~+CD25~+FoxP3~+调节性T细胞进入异位灶微环境及其在异位灶发生与发展中的调节作用。
1、趋化因子TECK及其受体CCR9在异位灶微环境的表达
本研究应用RT-PCR分析发现,异位灶CCR9的转录水平明显高于子宫内膜异位症患者的在位内膜及正常生育期妇女的子宫内膜。FCM方法检测子宫内膜异位症相关靶细胞CCR9的蛋白表达水平。ELISA方法检测子宫内膜异位症患者腹腔液TECK浓度及内异症相关细胞单独培养及共培养体系上清TECK的分泌。子宫内膜异位症患者腹腔液TECK水平明显升高。原代ESC比HPMC和U937分泌更高水平的TECK。ESC-U937共培养分泌的TECK明显高于ESC-HPMC和HPMC-U937共培养体系分泌的TECK;三者共培养进一步促进TECK的分泌,其中以三者直接接触共培养(U-E-H)最高;其分泌水平远远超过三种细胞单独培养的TECK分泌总量。在三种细胞直接或间接共培养不同组合中,HPMC/ESC-U937共培养体系的TECK分泌水平明显高于ESC/HPMC-U937和U937/ESC-HPMC体系的TECK分泌水平。这些结果提示,异位灶关联细胞共培养明显促进趋化因子TECK的分泌,可能参与子宫内膜异位症的发病。
2.17-β雌二醇和二噁英(TCDD)对异位症关联靶细胞趋化因子TECK及其受体CCR9表达的调控作用
通过异位灶关联细胞直接接触或间接接触共培养体系不同组合,观察17β-雌二醇及二噁英对共培养体系TECK/CCR9表达的调控作用。使用ELISA方法检测TECK的分泌;应用流式细胞术分析CCR9的表达。
低水平TCDD体外抑制ESC表达CCR9;而高水平TCDD则促进ESC表达CCR9。17B-E_2与TCDD联合处理ESC使CCR9表达上调;随着雌二醇浓度的升高,ESC表达CCR9的水平呈上升趋势。17β-E_2及TCDD对HPMC分泌TECK无明显影响。U937细胞分泌较高水平的TECK;经不同浓度17β-E_2体外处理后,0.01nM可以显著促进U937分泌TECK;但0.1nM-100nM均显著抑制U937分泌TECK。TCDD抑制U937细胞体外分泌TECK。17β-E_2联合TCDD可显著降低U937分泌TECK。17β-E2不影响ESC-HPMC分泌TECK;而TCDD促进其TECK分泌;17β-E2和TCDD联合处理较TCDD单独处理进一步增加TECK的分泌。17β-E_2不影响HPMC-U937培养体系分泌TECK;而TCDD也不明显影响其TECK分泌。17β-E_2与TCDD联合作用抑制H-U对TECK促分泌作用。TCDD促进ESC-HPMC-U937分泌TECK;17β-E2和TCDD联合处理较TCDD单独处理进一步增加TECK分泌。
以上研究结果表明,雌激素与TCDD通过对异位灶相关细胞TECK及CCR9的表达调控,参与子宫内膜异位症的发生与发展。
3、子宫内膜间质细胞与腹膜间皮细胞相互作用趋化CD4~+CD25~+FoxP3~+调节性T细胞并调控其功能
ESC-HPMC共培养通过分泌TECK促进CD4~+CD25~+T细胞的趋化;17β-雌二醇联合TCDD促进ESC对CD4~+CD25~+T细胞的趋化。重度子宫内膜异位症(γ-AFSⅢ,Ⅳ)患者腹腔液CD4~+FoxP3~+调节性T细胞的比例明显高于对照组及轻度子宫内膜异位症(γ-AFSⅠ,Ⅱ)。因此,子宫内膜间质细胞与腹膜间皮细胞相互作用,通过分泌趋化因子TECK介导CD4~+CD25~+T细胞的趋化。17β-雌二醇联合TCDD协同作用,进一步升调节TECK,促进CD4~+CD25~+T细胞的趋化。
子宫内膜间质细胞与腹膜间皮细胞过培养体系(ESC-HPMC)能诱导CD4~+CD25~+T细胞亚群显著扩增;17β-E_2及TCDD均明显放大ESC-HPMC对CD4~+CD25~+T细胞亚群的扩增作用;而抗TECK中和抗体可以部分拮抗这种扩增作用。子宫内膜间质细胞及腹膜间皮细胞显著升调节CD4~+CD25~+T细胞CTLA-4、FoxP3的表达;17β-E_2及TCDD17β-E_2及TCDD均明显放大ESC-HPMC对CD4~+CD25~+T细胞CTLA-4、FoxP3升调节作用;而抗TECK中和抗体可以部分拮抗这种升调节作用。子宫内膜间质细胞使CD4~+T细胞中CD25T细胞亚群比例下降和CD25~+T细胞亚群比例升高;共培养后CD4~+T细胞的增殖被明显抑制。与对照组及轻度子宫内膜异位症患者相比,重度子宫内膜异位症患者腹腔液IL-10及TGF-β1浓度均显著升高。子宫内膜间质细胞通过分泌趋化因子TECK抑制CD4~+CD25~+T细胞的凋亡。
以上研究结果表明,子宫内膜间质细胞种植于腹膜间皮细胞后,促进了CD4~+CD25~+T细胞亚群的显著性扩增,并升调节其免疫抑制功能,从而形成异位灶微环境免疫耐受特征。
4、CD4~+CD25~+FoxP3~+调节性T细胞促进对子宫内膜间质细胞侵袭
在ESC单独培养或与U937、CD4~+CD25~+T细胞及CD4~+CD25~-T细胞共培养的侵袭试验中,经TECK处理48h后,ESC侵袭性明显增加;而抗TECK中和抗体使ESC侵袭性明显下降。单独加入U937对ESC侵袭性无明显影响。CD4~+CD25~+T细胞或CD4~+CD25~-T细胞均可促进ESC的侵袭性。17β-雌二醇联合TCDD可以显著增加子宫内膜间质细胞的MMP2或MMP9的表达;TECK可进一步增加MMP2或MMP9的表达;而抗TECK抗体则可抑制ESC MMP2或MMP9的表达。单独培养的子宫内膜间质细胞或与HPMC共培养不表达MMP2或MMP9;而在与U937共培养后,MMP2或MMP9表达增加;CD4~+CD25~+T细胞或CD4~+CD25T细胞后,MMP2或MMP9表达进一步增加。因此,CD4~+CD25~+T细胞被趋化到异位灶局部后,促进了ESC的侵袭。
综上所述,异位灶关联细胞过表达趋化因子TECK及其受体CCR9;异位灶关联细胞共培养明显促进趋化因子TECK的分泌。17β-雌二醇与TCDD联合作用于异位灶相关细胞升调节TECK分泌及其受体CCR9的表达。子宫内膜间质细胞种植于腹膜间皮细胞后,通过升调节TECK促进CD4~+CD25~+调节性T细胞趋化到病灶局部;异位灶微环境增强CD4~+CD25~+调节性T细胞的免疫抑制功能。CD4~+CD25~+调节性T细胞被趋化到病灶局部后,形成免疫耐受微环境,并促进ESC侵袭。
The pathogenesis of endometriosis remains to be elucidated.According to Sampson's theory of ectopic transplantation of endometrium,the pelvic endometriosis is initiated by the retrograde menstruation when menstrual fragments flow out of the fimbriated end of the fallopian tubes,and become established on the ovarian surface or other sites in the peritoneal cavity.Since the retrograde menstruation is a physiological process occurring in a larger part of fertile women,other factors must be involved in the disease.Alteration/dysfunction of the serous immunity in the peritoneal cavity may lead to the occurrence and development of endometriosis
Current evidence suggests the peritoneal immune and inflammatory milieu might be associated with the pathogenesis of endometriosis.During the occurrence of endometriosis,the immune cells are recruited into the peritoneal cavity,and among them regulatory T cells may be critical in immune tolerance.The Tregs appear traffic to these tissues by depending on chemokine-chemokine receptor interactions.CCR9 was transcribed and translated significantly higher in the ectopic tissue than in the eutopic endometrium,and the latter is higher than in the normal fertile endometrium.CCR9/TECK interaction on the CD4~+T leads to activation of several intracellular signaling pathway, such as PI-3/Akt,MAPK/ERK,GSK-3β,and FKHR,and resistance to death stimuli from cycloheximide and Fas,which plays important roles in promoting the proliferation of T cells and escaping the cell apoptosis mediated by Fas.Chemokine is required in the process of recruiting circulating leukocytes into the pelvic and endometriotic sites.The functions of chemokines depend on binding to the corresponding receptors.To explore the role of chemokine TECK and its receptor CCR9 in the pathogenesis of endometriosis,we proposed the present study so as to understand pathogenesis of endometriosis.
Endometriosis is an estrogen-associate disease,environmental contaminants have been also suggested to play a role in the pathogenesis of endometriosis.Research on nonhuman primates has shown that exposure to the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD),an environmental contaminant,is associated with an increased prevalence and severity of endometriosis.Regulation of dioxin and estrogen in chemokines TECK and their receptors CCR9 expression and in the recruiting of the CD4~+CD25~+T cells into the endometriotic milieu will throw a light in elucidating the involvement of the chemokines in the etiology and pathogenesis of endometriosis.
1.The expression of chemokine TECK and its receptor CCR9 in the endometriotic milieu
CCR9 expression was analyzed by semi-quantified RT-PCR,and flow cytometry, respectively.CCR9 expression in the ectopic sites is significantly higher than that of the eutopic endometrium.TECK concentration in the peritoneal fluid and different contact and non-contact co-culture model of the endometriotic-associated cells were analyzed by ELISA.It has been found that TECK concentration in the peritoneal fluid from endometriosis is significantly higher than that of the normal fertile women. TECK secretion by ESC is higher than that of HPMC,a serous membrane cell line, and U937,a monocyte line.The co-culture of ESC-U937 secrets more TECK than that of ESC-HPMC and HPMC-U937.The co-culture of three cells further promotes secretion of TECK.Among the three kinds of contact co-culture of three cells,the co-culture of HPMC/ESC-U937 secrets more TECK than that of the ESC/HPMC-U937 and U937/ESC-HPMC.The three kinds of non-contact co-culture of the three cells secret less TECK than that of the contact co-culture.It is suggested that interaction of the endometriotic-associated cells significantly promotes the chemokine TECK secretion,which may play a role in the pathogenesis of endometriosis.
2.The regulatory effect of 17β-estradiol and TCDD on chemokine TECK and its receptor CCR9 expression in the endometriotic-associated cells
The different direct and indirect co-culture models of the endometriotic-associated cells such as ESC,HPMC and U937 cells were used to explore the effect of 17β-estradiol or/and TCDD on expression of chemokine TECK and its receptor CCR9 by using ELISA or FCM,respectively.We have found low dose of TCDD inhibits CCR9 expression by ESC in vitro,but high dose of TCDD promotes CCR9 expression in vitro in ESC.The combination of 17β-estradiol with TCDD increases CCR9 expression in ESC,and the increase is related positively to the concentration of 17β-estradiol.The 17β-estradiol or TCDD has no effect on TECK secretion by HPMC. U937 cells secret higher TECK than HPMC.Among the treatment with different concentration of 17β-estradiol,0.01nM promotes the TECK secretion by U937,but 0.1-100 nM significantly inhibit the TECK secretion by U937,and TCDD inhibits TECK secretion by U937.Combination of 17-estradiol with TCDD can significantly decrease TECK secretion by U937.17-estradiol has no effect on TECK secretion by the co-culture of ESC-HPMC,but TCDD promotes TECK secretion by the co-culture, and combination of 17-estradiol with TCDD further increases TECK secretion in the co-culture.Neither 17β-estradiol nor TCDD has any effect on TECK secretion by the co-culture of HPMC-U937,and combination of 17-estradiol with TCDD counteracts to the promotion of TECK in the co-culture.TCDD promotes TECK secretion in the contact co-culture of ESC-HPMC-U937,and combination of 17-estradiol with TCDD further increases TECK secretion in the contact co-culture.It is suggested that combination 17-βestradiol with TCDD promotes TECK secretion and CCR9 expression in the endometriotic-associated cells owing to the interaction of these cells, which is involved in the pathogenesis of endometriosis.
3.The endometrial stromal cells recruit CD4~+CD25~+FoxP3~+ regulatory T cells into the endometriotic milieu via secreting TECK and regulate their functions
The co-culture of ESC-HPMC promotes chemotaxis of CD4~+CD25~+FoxP3~+ regulatory T cells.The combination of 17-estradiol with TCDD promotes the chemotaxis of CD4~+CD25~+FoxP3~+ regulatory T cells into ectopic milieu containing ESCs.The CD4~+FoxP3~+ regulatory T cells in the peritoneal fluid of the advanced endometriosis(γ-AFSⅢ,Ⅳ)is higher than that of the early endometriosis (γ-AFSⅠ,Ⅱ)and the control without endometriosis.It is suggested ESCs mediate recruitment of the CD4~+CD25~+ regulatory T cells through secreting chemokine TECK after implanted on the HPMC,and combination of 17-estradiol with TCDD promotes chemotaxis of CD4~+CD25~+ regulatory T cells through up-regulating chemokine TECK secretion.
After co-cultured with ESC and HPMC respectively,CD4~+CD25~+ T cells are significantly expanded,and 17-estradiol or/and TCDD amplify the effect,but anti-TECK neutralizing antibody only partly inhibits the effect.After co-cultured with ESC or HPMC,CTLA-4 and FoxP3 expression in the CD4~+CD25~+ T cells increases significantly,and 17-estradiol or/and TCDD amplify the effect,but anti-TECK neutralizing antibody only partly inhibits the effect.Meanwhile in the presence of ESC,the CD25~-T cell subset decreases,and the CD25~+T cell subset increases. Concentration of IL-10 and TGF-β1 in the advanced endometriosis are also significantly higher than that of the early endometriosis and the control.ESCs only partly inhibit the apoptosis of CD4~+CD25~+ regulatory T cells through secreting chemokine TECK.It is suggested that ESCs aider implanted on HPMC promote the differentiation,expansion and function of CD4~+CD25~+ regulatory T cells,which maintain the local immunotolerance in the ectopic milieu.
4.The CD4~+CD25~+FoxP3~+ regulatory T cells enhance invasiveness of ESCs in the endometriotic milieu
Invasion assay shows that the co-culture of ESC/HPMC-U937-CD4~+CD25~+T cells or ESC/HPMC-U937-CD4~+CD25~-T cells increases invasiveness,activity and protein of MMP2,9 of ESCs that is promoted further by TECK,and inhibited by anti-TECK neutralizing antibody.Moreover,combination of 17-estradiol with TCDD significantly increases the expression of MMP2 and MMP9 in ESC in the co-culture. Therefore,the CD4~+CD25~+ regulatory T cells promote invasiveness of ESC in the ectopic milieu through interaction with the endometriotic-associated cells.
In conclusion,it has been demonstrated in the present study that the co-culture of the endometriotic-associated cells promotes TECK secretion,and combination of 17-estradiol with TCDD further promotes TECK secretion and CCR9 expression in the endometriotic-associated cells,which in turn recruits CD4~+CD25~+ regulatory T cells into the ectopic milieu,induces differentiation,and improves suppressive function of the regulatory T cells.The CD4~+CD25~+ regulatory T cells then promote invasiveness of ESC in the ectopic milieu,which is involved in the pathogenesis of endometriosis.
在子宫内膜异位症的发生和发展过程中,多种免疫细胞被募集到腹膜腔内,特别是单核巨噬细胞、T细胞亚群;且功能发生异常改变。调节性T细胞在维持免疫耐受中发挥至关重要的调节作用,在体内被趋化因子-趋化因子受体趋化到靶器官及组织,形成有利于免疫耐受的特殊免疫微环境。由于趋化因子及其受体TECK/CCR9在EMT在位内膜及异位内膜异常表达,故可能参与EMT的发生与发展。目前已知:CCR9与TECK的相互作用激活了CD4~+T细胞多种信号通路:MAPK(Mitogen-activated protein kinase)、P13k(Phosphoinositide-3 kinase)、蛋白激酶B、GSK-3β(Glycogen synthase kinase 3β)以及转录因子NF-κB,在促进T细胞的存活和增殖以及逃避Fas介导的细胞凋亡中起重要调控作用。
EMs的发病受多种因素影响:一方面,EMs是一种雌激素依赖性疾病;另一方面,环境污染物参与EMs的发病。含碳和氯燃料所产生的二噁英(TCDD)是全球普遍存在的最严重的大气污染物,可在大气中长期稳定存在。许多研究证据表明,TCDD与EMs的发病具有相关性。TCDD的亲脂特性决定其不易从尿中排泄而在体内脂肪中长期堆积,作用机制与甾体激素类似,通过与细胞内特异受体结合形成复合物,作为转录因子调控多种蛋白质分子表达。TCDD具有抗雌激素和雌激素样双重作用特性;依据年龄、月经周期、组织和其它因素变化所致的体内雌激素水平,决定着TCDD发挥雌激素效应,或抗雌激素效应。
本研究假设是:环境污染物TCDD与体内雌激素协同作用,导致腹腔内分泌-及免疫微环境改变。因此,我们通过体外构建异位灶模型,探索17β-E_2和TCDD通过调控异位灶相关细胞趋化因子TECK的分泌,进而募集CD4~+CD25~+FoxP3~+调节性T细胞进入异位灶微环境及其在异位灶发生与发展中的调节作用。
1、趋化因子TECK及其受体CCR9在异位灶微环境的表达
本研究应用RT-PCR分析发现,异位灶CCR9的转录水平明显高于子宫内膜异位症患者的在位内膜及正常生育期妇女的子宫内膜。FCM方法检测子宫内膜异位症相关靶细胞CCR9的蛋白表达水平。ELISA方法检测子宫内膜异位症患者腹腔液TECK浓度及内异症相关细胞单独培养及共培养体系上清TECK的分泌。子宫内膜异位症患者腹腔液TECK水平明显升高。原代ESC比HPMC和U937分泌更高水平的TECK。ESC-U937共培养分泌的TECK明显高于ESC-HPMC和HPMC-U937共培养体系分泌的TECK;三者共培养进一步促进TECK的分泌,其中以三者直接接触共培养(U-E-H)最高;其分泌水平远远超过三种细胞单独培养的TECK分泌总量。在三种细胞直接或间接共培养不同组合中,HPMC/ESC-U937共培养体系的TECK分泌水平明显高于ESC/HPMC-U937和U937/ESC-HPMC体系的TECK分泌水平。这些结果提示,异位灶关联细胞共培养明显促进趋化因子TECK的分泌,可能参与子宫内膜异位症的发病。
2.17-β雌二醇和二噁英(TCDD)对异位症关联靶细胞趋化因子TECK及其受体CCR9表达的调控作用
通过异位灶关联细胞直接接触或间接接触共培养体系不同组合,观察17β-雌二醇及二噁英对共培养体系TECK/CCR9表达的调控作用。使用ELISA方法检测TECK的分泌;应用流式细胞术分析CCR9的表达。
低水平TCDD体外抑制ESC表达CCR9;而高水平TCDD则促进ESC表达CCR9。17B-E_2与TCDD联合处理ESC使CCR9表达上调;随着雌二醇浓度的升高,ESC表达CCR9的水平呈上升趋势。17β-E_2及TCDD对HPMC分泌TECK无明显影响。U937细胞分泌较高水平的TECK;经不同浓度17β-E_2体外处理后,0.01nM可以显著促进U937分泌TECK;但0.1nM-100nM均显著抑制U937分泌TECK。TCDD抑制U937细胞体外分泌TECK。17β-E_2联合TCDD可显著降低U937分泌TECK。17β-E2不影响ESC-HPMC分泌TECK;而TCDD促进其TECK分泌;17β-E2和TCDD联合处理较TCDD单独处理进一步增加TECK的分泌。17β-E_2不影响HPMC-U937培养体系分泌TECK;而TCDD也不明显影响其TECK分泌。17β-E_2与TCDD联合作用抑制H-U对TECK促分泌作用。TCDD促进ESC-HPMC-U937分泌TECK;17β-E2和TCDD联合处理较TCDD单独处理进一步增加TECK分泌。
以上研究结果表明,雌激素与TCDD通过对异位灶相关细胞TECK及CCR9的表达调控,参与子宫内膜异位症的发生与发展。
3、子宫内膜间质细胞与腹膜间皮细胞相互作用趋化CD4~+CD25~+FoxP3~+调节性T细胞并调控其功能
ESC-HPMC共培养通过分泌TECK促进CD4~+CD25~+T细胞的趋化;17β-雌二醇联合TCDD促进ESC对CD4~+CD25~+T细胞的趋化。重度子宫内膜异位症(γ-AFSⅢ,Ⅳ)患者腹腔液CD4~+FoxP3~+调节性T细胞的比例明显高于对照组及轻度子宫内膜异位症(γ-AFSⅠ,Ⅱ)。因此,子宫内膜间质细胞与腹膜间皮细胞相互作用,通过分泌趋化因子TECK介导CD4~+CD25~+T细胞的趋化。17β-雌二醇联合TCDD协同作用,进一步升调节TECK,促进CD4~+CD25~+T细胞的趋化。
子宫内膜间质细胞与腹膜间皮细胞过培养体系(ESC-HPMC)能诱导CD4~+CD25~+T细胞亚群显著扩增;17β-E_2及TCDD均明显放大ESC-HPMC对CD4~+CD25~+T细胞亚群的扩增作用;而抗TECK中和抗体可以部分拮抗这种扩增作用。子宫内膜间质细胞及腹膜间皮细胞显著升调节CD4~+CD25~+T细胞CTLA-4、FoxP3的表达;17β-E_2及TCDD17β-E_2及TCDD均明显放大ESC-HPMC对CD4~+CD25~+T细胞CTLA-4、FoxP3升调节作用;而抗TECK中和抗体可以部分拮抗这种升调节作用。子宫内膜间质细胞使CD4~+T细胞中CD25T细胞亚群比例下降和CD25~+T细胞亚群比例升高;共培养后CD4~+T细胞的增殖被明显抑制。与对照组及轻度子宫内膜异位症患者相比,重度子宫内膜异位症患者腹腔液IL-10及TGF-β1浓度均显著升高。子宫内膜间质细胞通过分泌趋化因子TECK抑制CD4~+CD25~+T细胞的凋亡。
以上研究结果表明,子宫内膜间质细胞种植于腹膜间皮细胞后,促进了CD4~+CD25~+T细胞亚群的显著性扩增,并升调节其免疫抑制功能,从而形成异位灶微环境免疫耐受特征。
4、CD4~+CD25~+FoxP3~+调节性T细胞促进对子宫内膜间质细胞侵袭
在ESC单独培养或与U937、CD4~+CD25~+T细胞及CD4~+CD25~-T细胞共培养的侵袭试验中,经TECK处理48h后,ESC侵袭性明显增加;而抗TECK中和抗体使ESC侵袭性明显下降。单独加入U937对ESC侵袭性无明显影响。CD4~+CD25~+T细胞或CD4~+CD25~-T细胞均可促进ESC的侵袭性。17β-雌二醇联合TCDD可以显著增加子宫内膜间质细胞的MMP2或MMP9的表达;TECK可进一步增加MMP2或MMP9的表达;而抗TECK抗体则可抑制ESC MMP2或MMP9的表达。单独培养的子宫内膜间质细胞或与HPMC共培养不表达MMP2或MMP9;而在与U937共培养后,MMP2或MMP9表达增加;CD4~+CD25~+T细胞或CD4~+CD25T细胞后,MMP2或MMP9表达进一步增加。因此,CD4~+CD25~+T细胞被趋化到异位灶局部后,促进了ESC的侵袭。
综上所述,异位灶关联细胞过表达趋化因子TECK及其受体CCR9;异位灶关联细胞共培养明显促进趋化因子TECK的分泌。17β-雌二醇与TCDD联合作用于异位灶相关细胞升调节TECK分泌及其受体CCR9的表达。子宫内膜间质细胞种植于腹膜间皮细胞后,通过升调节TECK促进CD4~+CD25~+调节性T细胞趋化到病灶局部;异位灶微环境增强CD4~+CD25~+调节性T细胞的免疫抑制功能。CD4~+CD25~+调节性T细胞被趋化到病灶局部后,形成免疫耐受微环境,并促进ESC侵袭。
The pathogenesis of endometriosis remains to be elucidated.According to Sampson's theory of ectopic transplantation of endometrium,the pelvic endometriosis is initiated by the retrograde menstruation when menstrual fragments flow out of the fimbriated end of the fallopian tubes,and become established on the ovarian surface or other sites in the peritoneal cavity.Since the retrograde menstruation is a physiological process occurring in a larger part of fertile women,other factors must be involved in the disease.Alteration/dysfunction of the serous immunity in the peritoneal cavity may lead to the occurrence and development of endometriosis
Current evidence suggests the peritoneal immune and inflammatory milieu might be associated with the pathogenesis of endometriosis.During the occurrence of endometriosis,the immune cells are recruited into the peritoneal cavity,and among them regulatory T cells may be critical in immune tolerance.The Tregs appear traffic to these tissues by depending on chemokine-chemokine receptor interactions.CCR9 was transcribed and translated significantly higher in the ectopic tissue than in the eutopic endometrium,and the latter is higher than in the normal fertile endometrium.CCR9/TECK interaction on the CD4~+T leads to activation of several intracellular signaling pathway, such as PI-3/Akt,MAPK/ERK,GSK-3β,and FKHR,and resistance to death stimuli from cycloheximide and Fas,which plays important roles in promoting the proliferation of T cells and escaping the cell apoptosis mediated by Fas.Chemokine is required in the process of recruiting circulating leukocytes into the pelvic and endometriotic sites.The functions of chemokines depend on binding to the corresponding receptors.To explore the role of chemokine TECK and its receptor CCR9 in the pathogenesis of endometriosis,we proposed the present study so as to understand pathogenesis of endometriosis.
Endometriosis is an estrogen-associate disease,environmental contaminants have been also suggested to play a role in the pathogenesis of endometriosis.Research on nonhuman primates has shown that exposure to the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD),an environmental contaminant,is associated with an increased prevalence and severity of endometriosis.Regulation of dioxin and estrogen in chemokines TECK and their receptors CCR9 expression and in the recruiting of the CD4~+CD25~+T cells into the endometriotic milieu will throw a light in elucidating the involvement of the chemokines in the etiology and pathogenesis of endometriosis.
1.The expression of chemokine TECK and its receptor CCR9 in the endometriotic milieu
CCR9 expression was analyzed by semi-quantified RT-PCR,and flow cytometry, respectively.CCR9 expression in the ectopic sites is significantly higher than that of the eutopic endometrium.TECK concentration in the peritoneal fluid and different contact and non-contact co-culture model of the endometriotic-associated cells were analyzed by ELISA.It has been found that TECK concentration in the peritoneal fluid from endometriosis is significantly higher than that of the normal fertile women. TECK secretion by ESC is higher than that of HPMC,a serous membrane cell line, and U937,a monocyte line.The co-culture of ESC-U937 secrets more TECK than that of ESC-HPMC and HPMC-U937.The co-culture of three cells further promotes secretion of TECK.Among the three kinds of contact co-culture of three cells,the co-culture of HPMC/ESC-U937 secrets more TECK than that of the ESC/HPMC-U937 and U937/ESC-HPMC.The three kinds of non-contact co-culture of the three cells secret less TECK than that of the contact co-culture.It is suggested that interaction of the endometriotic-associated cells significantly promotes the chemokine TECK secretion,which may play a role in the pathogenesis of endometriosis.
2.The regulatory effect of 17β-estradiol and TCDD on chemokine TECK and its receptor CCR9 expression in the endometriotic-associated cells
The different direct and indirect co-culture models of the endometriotic-associated cells such as ESC,HPMC and U937 cells were used to explore the effect of 17β-estradiol or/and TCDD on expression of chemokine TECK and its receptor CCR9 by using ELISA or FCM,respectively.We have found low dose of TCDD inhibits CCR9 expression by ESC in vitro,but high dose of TCDD promotes CCR9 expression in vitro in ESC.The combination of 17β-estradiol with TCDD increases CCR9 expression in ESC,and the increase is related positively to the concentration of 17β-estradiol.The 17β-estradiol or TCDD has no effect on TECK secretion by HPMC. U937 cells secret higher TECK than HPMC.Among the treatment with different concentration of 17β-estradiol,0.01nM promotes the TECK secretion by U937,but 0.1-100 nM significantly inhibit the TECK secretion by U937,and TCDD inhibits TECK secretion by U937.Combination of 17-estradiol with TCDD can significantly decrease TECK secretion by U937.17-estradiol has no effect on TECK secretion by the co-culture of ESC-HPMC,but TCDD promotes TECK secretion by the co-culture, and combination of 17-estradiol with TCDD further increases TECK secretion in the co-culture.Neither 17β-estradiol nor TCDD has any effect on TECK secretion by the co-culture of HPMC-U937,and combination of 17-estradiol with TCDD counteracts to the promotion of TECK in the co-culture.TCDD promotes TECK secretion in the contact co-culture of ESC-HPMC-U937,and combination of 17-estradiol with TCDD further increases TECK secretion in the contact co-culture.It is suggested that combination 17-βestradiol with TCDD promotes TECK secretion and CCR9 expression in the endometriotic-associated cells owing to the interaction of these cells, which is involved in the pathogenesis of endometriosis.
3.The endometrial stromal cells recruit CD4~+CD25~+FoxP3~+ regulatory T cells into the endometriotic milieu via secreting TECK and regulate their functions
The co-culture of ESC-HPMC promotes chemotaxis of CD4~+CD25~+FoxP3~+ regulatory T cells.The combination of 17-estradiol with TCDD promotes the chemotaxis of CD4~+CD25~+FoxP3~+ regulatory T cells into ectopic milieu containing ESCs.The CD4~+FoxP3~+ regulatory T cells in the peritoneal fluid of the advanced endometriosis(γ-AFSⅢ,Ⅳ)is higher than that of the early endometriosis (γ-AFSⅠ,Ⅱ)and the control without endometriosis.It is suggested ESCs mediate recruitment of the CD4~+CD25~+ regulatory T cells through secreting chemokine TECK after implanted on the HPMC,and combination of 17-estradiol with TCDD promotes chemotaxis of CD4~+CD25~+ regulatory T cells through up-regulating chemokine TECK secretion.
After co-cultured with ESC and HPMC respectively,CD4~+CD25~+ T cells are significantly expanded,and 17-estradiol or/and TCDD amplify the effect,but anti-TECK neutralizing antibody only partly inhibits the effect.After co-cultured with ESC or HPMC,CTLA-4 and FoxP3 expression in the CD4~+CD25~+ T cells increases significantly,and 17-estradiol or/and TCDD amplify the effect,but anti-TECK neutralizing antibody only partly inhibits the effect.Meanwhile in the presence of ESC,the CD25~-T cell subset decreases,and the CD25~+T cell subset increases. Concentration of IL-10 and TGF-β1 in the advanced endometriosis are also significantly higher than that of the early endometriosis and the control.ESCs only partly inhibit the apoptosis of CD4~+CD25~+ regulatory T cells through secreting chemokine TECK.It is suggested that ESCs aider implanted on HPMC promote the differentiation,expansion and function of CD4~+CD25~+ regulatory T cells,which maintain the local immunotolerance in the ectopic milieu.
4.The CD4~+CD25~+FoxP3~+ regulatory T cells enhance invasiveness of ESCs in the endometriotic milieu
Invasion assay shows that the co-culture of ESC/HPMC-U937-CD4~+CD25~+T cells or ESC/HPMC-U937-CD4~+CD25~-T cells increases invasiveness,activity and protein of MMP2,9 of ESCs that is promoted further by TECK,and inhibited by anti-TECK neutralizing antibody.Moreover,combination of 17-estradiol with TCDD significantly increases the expression of MMP2 and MMP9 in ESC in the co-culture. Therefore,the CD4~+CD25~+ regulatory T cells promote invasiveness of ESC in the ectopic milieu through interaction with the endometriotic-associated cells.
In conclusion,it has been demonstrated in the present study that the co-culture of the endometriotic-associated cells promotes TECK secretion,and combination of 17-estradiol with TCDD further promotes TECK secretion and CCR9 expression in the endometriotic-associated cells,which in turn recruits CD4~+CD25~+ regulatory T cells into the ectopic milieu,induces differentiation,and improves suppressive function of the regulatory T cells.The CD4~+CD25~+ regulatory T cells then promote invasiveness of ESC in the ectopic milieu,which is involved in the pathogenesis of endometriosis.
引文
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