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.
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米非司酮通过 ERK 激活作为糖皮质激素拮抗剂，增加子宫自然杀伤细胞的细胞毒性
DOI：
10.1371/journal.pone.0036413
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Chen Y;Wang Y;Zhuang Y;Zhou F;Huang L
米非司酮（RU486）是一种强效黄体酮和糖皮质激素拮抗剂，参与免疫调节。我们之前的研究表明，米非司酮直接增强人子宫自然杀伤细胞（uNK）的细胞毒性。然而，细胞毒性增加的机制尚不清楚。在这里，我们探讨了米非司酮产生的uNK细胞毒性增加是否由于抗孕酮或抗糖皮质激素活性，并研究了丝裂原活化蛋白激酶（MAPK）途径的相关变化。方法/主要发现子宫NK细胞从蜕膜样品中分离出来，与不同浓度的黄体酮、皮质醇或米非司酮孵育。采用线粒体乳酸脱氢酶MTS染色和流式细胞术检测uNK细胞的细胞毒性和穿孔素表达。Western blot检测MAPK信号通路组分的磷酸化。皮质醇以浓度依赖的方式减弱uNK细胞介导的细胞毒性，而黄体酮则没有作用。单独使用米非司酮可增加uNK细胞的细胞毒性和穿孔素的表达；这些影响被皮质醇阻断了。此外，米非司酮以可的松可逆的方式增加ERK1/2的磷酸化。特异性ERK1/2抑制剂PD98059或U0126阻断了uNK细胞中皮质醇和米非司酮诱导的反应。结论/意义这些结果表明，米非司酮作为糖皮质激素拮抗剂通过ERK激活来增强uNK细胞介导的细胞毒性，这可能是由穿孔素表达增加引起的。这些观察结果可能揭示了米非司酮上调uNK细胞毒性的重要机制。
Background Mifepristone (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 Findings Uterine 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/Significance These 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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影响因子：
20.3
作者：
Chiossone, Laura;Vitale, Chiara;Mingari, Maria Cristina
通讯作者：
Mingari, Maria Cristina
人子宫内膜基质细胞来源的条件培养基对子宫自然杀伤（uNK）细胞增殖和细胞毒性的影响
DOI：
10.1111/j.1600-0897.2010.00955.x
发表时间：
2011-06-01
影响因子：
3.6
作者：
Chen, Yuezhou;Zhuang, Yaling;Huang, Lili
通讯作者：
Huang, Lili
DOI：
10.1016/0002-9378(92)91835-x
发表时间：
1992-01-01
影响因子：
9.8
作者：
HANSEN, KA;OPSAHL, MS;KLEIN, TA
通讯作者：
KLEIN, TA
影响因子：
4.8
作者：
Imasato, A;Desbois-Mouthon, C;Li, JD
通讯作者：
Li, JD
影响因子：
6.7
作者：
Li, AM;Felix, JC;Jain, JK
通讯作者：
Jain, JK