Mifepristone regulates Tregs function mediated by dendritic cells through suppressing the expression of TGF-β

Li, Yinghua; Cao, Lili; Qian, Zhida; Guo, Qianjin; Niu, Xiaocen; Li-li, Huang

doi:10.1080/08923973.2020.1867998

Cited by 6 publications

(7 citation statements)

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“…Jaya et al reported that the level of uterine monocyte chemotactic protein-3 (MCP3), a pro-inflammatory and Th1 effector, was increased after the administration of mifepristone [31]. Additionally, Li Y et al suggested that mifepristone regulates DC function by decreasing TGF-β expression in vitro, which further results in the downregulation of FOXP3 and IL-10 in Tregs [32]. Notably, progesterone suppresses IL-17 expression [33,34].…”

Section: Introductionmentioning

confidence: 99%

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Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves embryo implantation in mice by regulating local Treg/Th17 cell balance

Fan

Sha

et al. 2021

Journal of Reproduction and Development

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Immune imbalance of Treg/Th17 cells may contribute to recurrent implantation failure (RIF) during in vitro fertilization and embryo transfer (IVF-ET). In this study, we sought to determine the effect of intrauterine administration of mouse PBMCs prior to embryo implantation on endometrial receptivity and embryo implantation, and examine the underlying mechanism of Treg/Th17 cell balance following intrauterine administration of PBMCs. Pregnant mice were randomly divided into three groups: control group, embryo implantation dysfunction (EID) group, and EID with PBMCs group, and the number of embryo implantation sites was recorded during early pregnancy (Pd7.5). The balance of Treg/Th17 cells in the peripheral blood, spleen, and local implantation sites was detected during the peri-implantation period (Pd4.0) and early pregnancy (Pd7.5). The EID group demonstrated a significant decrease in the number of embryo implantation sites, while the EID with PBMCs group demonstrated higher number of embryo implantation sites compared to the EID group. The balance of Treg/Th17 cells in the peripheral blood and spleen tissues was not significantly different between the aforementioned groups. However, the local uterine ratio of the Treg/Th17 cells increased in the EID with PBMCs group compared to that in the EID group. Collectively, we found that intrauterine administration of PBMCs prior to embryo implantation effectively promotes embryo implantation rates. This may be attributed to the improvement in the local immune balance of Treg and Th17 cells compared with the overall immune balance.

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Section: Introductionmentioning

confidence: 99%

“…Additionally, Li Y et al . suggested that mifepristone regulates DC function by decreasing TGF-β expression in vitro , which further results in the downregulation of Foxp3 and IL-10 in Tregs [ 32 ]. Notably, progesterone suppresses IL-17 expression [ 33 , 34 ].…”

mentioning

confidence: 99%

Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves embryo implantation in mice by regulating local Treg/Th17 cell balance

Fan

Sha

et al. 2021

Journal of Reproduction and Development

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“…It has been shown that mifepristone exerts its effect by shifting immunological elements by enhancing the expression of cytotoxic lymphocytes [ 54 ], increasing the cytotoxicity of peripheral blood NK cells [ 55 ] and uterine NK cells [ 56 ], and enhancing antigen-specific CD4 + and CD8 + T cell inflammatory cytokines (IFN-γ) and cytotoxic molecule release (granzyme B) [ 57 ]. Mifepristone regulates Treg function mediated by dendritic cells by inhibiting the expression of TGF-β [ 58 ]. The results of our current study imply that mifepristone may play a therapeutic role in adenomyosis by inhibiting the expression of these four immunomodulatory molecules, improving the immune microenvironment status of the uterus and effectively inhibiting or clearing ectopic endometrial cells.…”

Section: Discussionmentioning

confidence: 99%

Mifepristone inhibited the expression of B7-H2, B7-H3, B7-H4 and PD-L2 in adenomyosis

Qin

Sun

Wang

et al. 2021

Reprod Biol Endocrinol

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Background The immune mechanism was shown to be involved in the development of adenomyosis. The aim of the current study was to evaluate the expression of the immune checkpoints B7-H2, B7-H3, B7-H4 and PD-L2 in adenomyosis and to explore the effect of mifepristone on the expression of these immune checkpoints. Methods The expression of B7-H2, B7-H3, B7-H4 and PD-L2 in normal endometria and adenomyosis patient samples treated with or without mifepristone was determined by immunohistochemistry analysis. Results In adenomyosis patient samples, the expression of B7-H2, B7-H3 and B7-H4 was increased in the eutopic and ectopic endometria compared with normal endometria, both in the proliferative and secretory phases. Moreover, the expression of B7-H2 and B7-H3 was higher in adenomyotic lesions than in the corresponding eutopic endometria, both in the proliferative and secretory phases. The expression of PD-L2 was higher in adenomyotic lesions than in normal endometria in both the proliferative and secretory phases. In the secretory phase but not the proliferative phase, the expression of B7-H4 and PD-L2 in adenomyotic lesions was significantly higher than that in the corresponding eutopic endometria. In normal endometria and eutopic endometria, the expression of B7-H4 was elevated in the proliferative phase compared with that in the secretory phase, while in the ectopic endometria, B7-H4 expression was decreased in the proliferative phase compared with the secretory phase. In addition, the expression of B7-H2, B7-H3, B7-H4 and PD-L2 was significantly decreased in adenomyosis tissues after treatment with mifepristone. Conclusions The expression of the immune checkpoint proteins B7-H2, B7-H3, B7-H4 and PD-L2 is upregulated in adenomyosis tissues and is downregulated with mifepristone treatment. The data suggest that B7 immunomodulatory molecules are involved in the pathophysiology of adenomyosis.

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“…Isolation and Culture of Monocyte-Derived DCs: Monocyte-derived DCs were prepared as described in the previous literatures. [30,11] In brief, whole venous blood derived from healthy donors (obtained from the local central blood bank, n = 5) was density gradient centrifuged with Histopaque-1077 (Sigma-Aldrich, St. Louis, MO) to isolate peripheral blood mononuclear cells, which were enriched with Dynabeads CD14 (Miltenyi Biotec, Bergisch Gladbach, Germany) on an autoMACS Pro Separator to harvest CD14 + monocytes. CD14 + cells (purity >90%) cultured in RPMI 1640 (no phenol red, Gibco, Grand Island, NY) supplemented with 10% fetal bovine serum (Charcoal-Stripped, Hyclone, Logan, UT) were further stimulated with 100 ng mL −1 granulocyte-macrophage colony-stimulating factor (GM-CSF) and 20 ng mL −1 interleukin-4 (IL-4) (R&D Systems, Minneapolis, MN) for 6 days to induce the maturation of DCs.…”

Section: Methodsmentioning

confidence: 99%

“…Mifepristone-Stimulated DCs: Monocyte-derived DCs were further incubated with mifepristone or lipopolysaccharide (LPS), and the whole culture procedure and concentration choose followed our previous report. [11] Monocyte-derived DCs were incubated with various concentrations of mifepristone (20,65,200 nmol L −1 , Sigma) dissolved in dimethyl sulphoxide or 100 ng mL −1 LPS (Sigma-Aldrich) for a total of 48 h to induce the maturity. LPS treatment was used as a positive control.…”

Section: Methodsmentioning

confidence: 99%

Mifepristone Modulates the Polarization of Th1/Th2 by Inducing the Mature of Monocyte‐Derived Dendritic Cells

Li,

et al. 2023

Advanced Therapeutics

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As an anti‐implantation contraception medicine, mifepristone can alter the development of the endometrium. In contrast, little research has been performed to decipher the effect of mifepristone on Th1/Th2 immune homeostasis in the endometrium. CD14+ monocytes derived from healthy donors were cultured with interleukin‐4 (IL‐4) and granulocyte macrophage‐colony stimulating factor to induce monocyte‐derived dendritic cells (DCs), which were further incubated with mifepristone. Mifepristone incubation could induce up‐regulated CD83 and HLA‐DR staining on monocyte‐derived DCs. Functionally, mifepristone incubation could enhance the allostimulatory capacity of DCs to promote the proliferation of allogeneic T cells with up‐regulated Th1 cell proportion and down‐regulated Th2 cell proportion. On the other side, increased Th1 cytokines release (interferon‐γ, TNF‐α), inhibited Th2 cytokines release (IL‐10, IL‐4), promoted T‐Box transcription factor 21 transcription, and inhibited GATA binding protein 3 transcription were also identified. Mifepristone‐stimulated DCs could alter the Th1/Th2 transcription balance to favor Th1 skewing inflammatory environment.This article is protected by copyright. All rights reserved

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Mifepristone regulates Tregs function mediated by dendritic cells through suppressing the expression of TGF-β

Cited by 6 publications

References 50 publications

Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves embryo implantation in mice by regulating local Treg/Th17 cell balance

Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves embryo implantation in mice by regulating local Treg/Th17 cell balance

Mifepristone inhibited the expression of B7-H2, B7-H3, B7-H4 and PD-L2 in adenomyosis

Mifepristone Modulates the Polarization of Th1/Th2 by Inducing the Mature of Monocyte‐Derived Dendritic Cells

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