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

Abstract

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.

Endogenous TWEAK is critical for regulating the function of mouse uterine natural killer cells in an immunological model of pregnancy loss

“…These cells possess a unique receptor phenotype with latent cytotoxicity and produce various cytokines that are essential for survival of the fetus. Previous studies have demonstrated that although uNK cells are beneficial in regulating normal pregnancy, they can be transformed into detrimental cells in response to bacterial and viral infections . The LPS‐treated pregnant mice exhibited a significant decrease in the number of uNK cells, as well as a significant increase in the number of uterine pro‐inflammatory neutrophils .…”

Glucocorticoids and Reproduction: Traffic Control on the Road to Reproduction

“…During early pregnancy, uNK cells regulate trophoblast invasion and the vascular changes that support placental development. uNK cells express GR, and uNK cell-mediated cytotoxicity is sensitive cortisol treatment [82, 83]. Prednisolone treatment in women with recurrent miscarriage is associated with reduced numbers of uNK cells, although a link between the glucocorticoid-mediated reduction in uNK cell numbers and pregnancy success was not demonstrated [84].…”

Human Decidual Stromal Cells as a Component of the Implantation Niche and a Modulator of Maternal Immunity

“…The authors observed decreased mRNA levels of the enzyme 11 β HSD1 in ESC decidualized in vitro , which is consistent with the increased presence of CD56 + cells in the corresponding tissue. This enzyme is involved in the synthesis of cortisol, a potent inhibitor of uNK cell cytotoxicity [ 184 ]. Hence, it is possible that cortisol deprivation caused by 11 β HSD1 insufficiency in the stromal cells leads to the enrichment of activated NK cells, linked to low fertility status of the patients.…”