1-Methyl-tryptophan attenuates regulatory T cells differentiation due to the inhibition of estrogen-IDO1-MRC2 axis in endometriosis

作者：Chunyan Wei, Jie Mei, Lingli Tang, Yukai Liu, Da‐Jin Li, Ming‐Qing Li, Xiao‐Yong Zhu · 发表于：Cell Death and Disease · 年份：2016 · DOI：10.1038/cddis.2016.375 · 被引用次数：55 · 研究领域：Endometriosis Research and Treatment、Reproductive System and Pregnancy、Endometrial and Cervical Cancer Treatments

Abstract Foxp3 + regulatory T (T reg ) cells contribute to the local dysfunctional immune environment in endometriosis, an estrogen-dependent gynecological disease, which affects the function of ectopic endometrial tissue clearance by the immune system. The reason for the high percentage of peritoneal T reg in endometriosis patients is unknown. Here, we show that the proportion of peritoneal T reg cells increases as endometriosis progresses. To determine the probable mechanism, we established a naive T cell-macrophage-endometrial stromal cell (ESC) co-culture system to mimic the peritoneal cavity microenvironment. After adding 1-methyl-tryptophan (1-MT), a specific inhibitor of indoleamine 2,3-dioxygenase-1 (IDO1), to the co-culture system, we found that the differentiation of T reg cells, mainly IL-10 + T reg cells, decreased. Therefore, 1-MT-pretreated ESCs-educated T reg cells performed impaired suppressive function. Moreover, estrogen promoted the differentiation of T reg cells by elevating IDO1 expression in the ectopic lesion. Subsequently, we examined mannose receptor C, type 2 (MRC2), which is an up-stream molecule of IL-10, by bioinformatics analysis and real-time PCR validation. MRC2 expression in ectopic ESCs was notably lower than that in normal ESCs, which further negatively regulated the expression of IDO1 and Ki-67 in ESCs. Furthermore, MRC2 is required for T reg differentiation in the ectopic lesion, especially that for CD4 high T reg . Therefore, MRC2-silence...