SCM-198 Alleviates Endometriosis by Suppressing Estrogen-ERα mediated Differentiation and Function of CD4(+)CD25(+) Regulatory T Cells.
SCM-198 Alleviates Endometriosis by Suppressing Estrogen-ERα mediated Differentiation and Function of CD4(+)CD25(+) Regulatory T Cells.
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DOI：
10.7150/ijbs.68224
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发表时间：
2022
影响因子：
9.2
通讯作者：
Du MR
中科院分区：
文献类型：
--
作者：
Li YY;Lin YK;Li Y;Liu XH;Li DJ;Wang XL;Wang L;Zhu YZ;Yu M;Du MR
背景：子宫内膜异位症(EMS)是一种典型的内分泌免疫紊乱，与异位病灶雌激素分泌显著增加和免疫反应紊乱有关。子宫内膜异位症患者腹膜调节性T细胞(Tregs)的增殖及其在子宫内膜异位免疫耐受中的致病作用已有报道。局部高雌激素是否通过助孕Tregs促进EMS的发生，有待进一步探讨。到目前为止，还没有治疗EMS的有效药物。SCM-198是一种具有多种生理活性的人工合成益母草碱。SCM-198是否通过雌激素调节Tregs，促进EMS的根治尚未见报道。方法：采用流式细胞术分析EMS患者腹腔液中Tregs的比例。采用ELISA法和RTPCR法分别检测大鼠腹膜雌激素浓度和雌激素受体α(ERα)和雌激素受体β(ERβ)的基因表达水平。分组体外诱导实验，探讨SCM-198和雌激素信号转导对Tregs的影响。采用细胞侵袭力和细胞存活率检测SCM-198处理前后Tregs和异位内膜基质细胞(EESCs)之间的相互作用。此外，建立了EMS小鼠模型，以验证SCM-198的治疗作用。结果：内异症患者腹腔液中Tregs明显升高，并伴有雌激素受体α过度激活。雌激素受体α刺激Treg细胞及其细胞因子(IL-10和转化生长因子-β1)的产生，这种作用可被雌激素受体逆转。此外，SCM-198还减弱了Tregs增强的eESCs的侵袭力和活性。体内实验证实，SCM198可明显抑制异位病变的生长，并通过雌激素受体α失活下调Treg的功能。结论：SCM198通过抑制雌激素受体α信号通路抑制Tregs的扩张，为这类难治性疾病提供了一种有希望的治疗方法。
Background: Endometriosis (EMS), a typical endocrine immune disorder, associates with dramatically increased estrogen production and disorganized immune response in ectopic focus. Peritoneal regulatory T cells (Tregs) expansion in women with EMS and their pathogenic role attributable to endometriotic immunotolerance has been reported. Whether local high estrogen promotes EMS by discipling Tregs needs to be further explored. Up to date, there is no effective medicine for the treatment of EMS. SCM-198 is a synthetic leonurine with multiple physiological activities. Whether SCM-198 could regulate Tregs via estrogen and facilitate the radical cure of EMS has not yet been reported. Methods: Proportion of Tregs in peritoneal fluid of patients with EMS was firstly analyzed via flow cytometry. Peritoneal estrogen concentration and the mRNA levels of estrogen receptor α (ERα) and estrogen receptor β (ERβ) of Tregs were detected by ELISA and RT-PCR, respectively. Grouped in vitro induction assays were performed to explore the effects of SCM-198 and estrogen signaling on Tregs. Cell invasion and viability assays were utilized to detect the crosstalk between Tregs and ectopic endometrial stromal cells (eESCs), with or without SCM-198 treatment. Furthermore, EMS mice models were established to verify the therapeutic effects of SCM-198. Results: Increased Tregs were found in peritoneal fluid of EMS patients, accompanied with estrogen-ERα overactivation. Estrogen-ERα triggered the expansion of Tregs and their cytokine production (IL-10 and TGF-β1), which could be reversed by SCM-198 treatment. Moreover, SCM-198 abated the invasion and viability of eESCs enhanced by Tregs. In vivo experiments confirmed that SCM-198 obviously retarded the growth of ectopic lesions and downregulated the functions of Tregs via estrogen-ERα inactivation. Conclusions: These data suggest that SCM-198 attenuates Tregs expansion via the inhibition of estrogen-ERα signaling in EMS and offer a promising therapy for such a refractory disease.
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影响因子：
5
作者：
Missmer, SA;Hankinson, SE;Hunter, DJ
通讯作者：
Hunter, DJ
DOI：
10.1186/s12958-018-0325-2
发表时间：
2018-02-01
期刊：
Reproductive biology and endocrinology : RB&E
影响因子：
--
作者：
Hanada T;Tsuji S;Nakayama M;Wakinoue S;Kasahara K;Kimura F;Mori T;Ogasawara K;Murakami T
通讯作者：
Murakami T
SCM-198 通过 Bax/Bcl-2 和 ERK 信号通路保护子宫内膜基质细胞免受氧化损伤
影响因子：
3.7
作者：
Li, Yunyun;Lin, Yikong;Du, Meirong
通讯作者：
Du, Meirong
影响因子：
14.8
作者：
Fantini, Massimo C.;Dominitzki, Sabine;Becker, Christoph
通讯作者：
Becker, Christoph
影响因子：
6.7
作者：
Pluchino, Nicola;Mamillapalli, Ramanaiah;Taylor, Hugh S.
通讯作者：
Taylor, Hugh S.