Low-dose mifepristone increases uterine natural killer cell cytotoxicity and perforin expression during the receptive phase

Zhou, Feng; Chen, Xiuying; Zhuang, Yaling; Chen, Yuezhou; Huang, Lili

doi:10.1016/j.fertnstert.2011.06.074

Cited by 17 publications

(12 citation statements)

References 40 publications

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“…It has been reported that the mobilization and redistribution of perforin play an important role in the control of NK cytotoxicity [46]. In a previous study, we showed that in human endometrial explants, mifepristone increased expression of perforin and increased uNK cell-mediated cytotoxicity [14]. In the current study, we observed that the mifepristone-induced increase in perforin expression in uNK cells can be reversed by cortisol, which indicated that mifepristone could increase the expression of perforin through the GR.…”

Section: Discussionsupporting

confidence: 61%

“…Our previous studies showed that low-dose mifepristone increases the number of CD56 + -NK cells, and the percentages of the NK cell subset CD3 − CD56 + CD16 − in human endometrial explants [13]. Uterine NK cell-mediated cytotoxicity and perforin expression were also augmented by treatment with mifepristone [14]. The exact mechanisms responsible for immune modulation by mifepristone in uNK cells, however, are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Mifepristone Increases the Cytotoxicity of Uterine Natural Killer Cells by Acting as a Glucocorticoid Antagonist via ERK Activation

et al. 2012

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BackgroundMifepristone (RU486), a potent antagonist of progesterone and glucocorticoids, is involved in immune regulation. Our previous studies demonstrated that mifepristone directly augments the cytotoxicity of human uterine natural killer (uNK) cells. However, the mechanism responsible for this increase in cytotoxicity is not known. Here, we explored whether the increased cytotoxicity in uNK cells produced by mifepristone is due to either anti-progesterone or anti-glucocorticoid activity, and also investigated relevant changes in the mitogen-activated protein kinase (MAPK) pathway.Methodology/Principal FindingsUterine NK cells were isolated from decidual samples and incubated with different concentrations of progesterone, cortisol, or mifepristone. The cytotoxicity and perforin expression of uNK cells were detected by mitochondrial lactate dehydrogenase-based MTS staining and flow cytometry assays, respectively. Phosphorylation of components of the MAPK signaling pathway was detected by Western blot. Cortisol attenuated uNK cell-mediated cytotoxicity in a concentration-dependent manner whereas progesterone had no effect. Mifepristone alone increased the cytotoxicity and perforin expression of uNK cells; these effects were blocked by cortisol. Furthermore, mifepristone increased the phosphorylation of ERK1/2 in a cortisol-reversible manner. Specific ERK1/2 inhibitor PD98059 or U0126 blocked cortisol- and mifepristone-induced responses in uNK cells.Conclusions/SignificanceThese results suggest that mifepristone acts as a glucocorticoid antagonist to augment uNK cell-mediated cytotoxicity via ERK activation, which may be caused by increased perforin expression. These observations may reveal an important mechanism by which mifepristone upregulates the cytotoxicity of uNK cells.

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Mifepristone Increases the Cytotoxicity of Uterine Natural Killer Cells by Acting as a Glucocorticoid Antagonist via ERK Activation

et al. 2012

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“…We thus confirmed the findings of a previous report [16] that uNK cells are the most abundant class of lymphocytes present in gestational endometria. The present observation of increased activity of uNK cells by mifepristone during early pregnancy also extends from previous studies in the nonpregnant uterus [11]. However, a previous study showed that CTLs were not increased by mifepristone, which was inconsistent with our results [17].…”

Section: Discussioncontrasting

confidence: 77%

“…Mifepristone, synthetic 19-norsteroid, blocks the receptor of progesterone and weakens the progesterone function [11]. Misoprostol can induce cervical softening, thus enhancing the efficacy of the mifepristone as an abortifacient [12].…”

Section: Introductionmentioning

confidence: 99%

Roles of Mifepristone on the Regulation of Cytotoxic Lymphocytes and Regulatory T Cells

Liu

Zhou²,

Qin

et al. 2017

Gynecol Obstet Invest

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Objective: To investigate the immunologic function of mifepristone, which acts as a contraceptive drug at the level of the decidua. Setting: In our hospital, 60 women (less than 63 days of amenorrhea) volunteered to terminate their pregnancies by the uterine suction evacuation method. Immunohistochemically, the transcription factor forkhead box P3 and granzyme B staining were performed to identify regulatory T cells and cytotoxic lymphocytes (CLs) in all operational subjects. CD8 (cytotoxic T cells marker) and CD56 (natural killer cells marker) staining were further performed in order to characterize the CLs subpopulations. Result: A significantly increased number of CLs was found in the decidua treated with mifepristone. Conclusion: Mifepristone increases the expression of CLs in the decidua, and it provides new insights into the immunologic function of mifepristone as a drug used for pregnancy termination.

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“…As a key component of innate immunity, they not only participate in the early phase of immune responses against certain viruses, parasites, and microbial pathogens19, but also play an important role in the process of human pregnancy20. Substantial amounts of data support that uNK cells help to regulate pregnancy maintenance via several mechanisms, including the production of a variety of cytokines capable of directly influencing trophoblast growth and hormone production as well as implantation and vascularization of the decidua, producing immune modulatory proteins involved in immune regulation at the maternal-foetal interface, and control of trophoblast invasion via cell-mediated cytotoxicity2122.…”

Section: Discussionmentioning

confidence: 99%

Increased Uterine NK cell numbers and perforin expression during the implantation phase in IVF Cycles with GnRH Antagonist Protocol

Wang

Xia

et al. 2017

Sci Rep

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GnRH antagonist negatively affects endometrial receptivity in in vitro fertilization (IVF) cycles, however, its underlying mechanism remains unclear. To explore its target molecules, we studied endometria in the window phase of fixed GnRH antagonist, low-dose flexible GnRH antagonist, GnRH agonist long protocol, and untreated control groups. There were 384 differentially expressed genes (DEGs) in the fixed antagonist group with greater than twofold expression change compared with the control group and 197 DEGs between the fixed antagonist and agonist groups, the majority of which were associated with the natural killer (NK) cell-mediated cytotoxicity pathway. We then analysed the PRF1 and FASLG protein levels. The perforin level were significantly higher in both the antagonist groups than in other two groups, and was higher in the fixed antagonist group. Similarly, the uNK cell numbers were higher in the antagonist groups, and the highest uNK cell number occurred in the fixed group (p < 0.05). No significant differences existed in the Fas ligand levels and apoptosis rates among the three treatment groups, but were higher in the treatment groups than the control group. Together, these data indicate that GnRH antagonist may increase the uNK cell numbers and perforin expression, and this effect may be dose-dependent.

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Low-dose mifepristone increases uterine natural killer cell cytotoxicity and perforin expression during the receptive phase

Cited by 17 publications

References 40 publications

Mifepristone Increases the Cytotoxicity of Uterine Natural Killer Cells by Acting as a Glucocorticoid Antagonist via ERK Activation

Mifepristone Increases the Cytotoxicity of Uterine Natural Killer Cells by Acting as a Glucocorticoid Antagonist via ERK Activation

Roles of Mifepristone on the Regulation of Cytotoxic Lymphocytes and Regulatory T Cells

Increased Uterine NK cell numbers and perforin expression during the implantation phase in IVF Cycles with GnRH Antagonist Protocol

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