Mifepristone Augments uNK Cell-Cytotoxicity Figure 6. The increased cytotoxicity of uNK cells by mifepristone was inhibited by PD98059 or U0126. Before the treatment with cortisol 6 mifepristone, uNK cells were pretreated with PD98059 (A) or U0126 (B) for 30 min. They were then treated with mifepristone 6 cortisol for 24 h. Cells stimulated with IL-15 were used as positive control. The cytotoxicity of uNK cells was detected by the MTS assay. Data were analyzed using ANOVA and expressed as means 6 SEM. *, P,0.05. doi:10.1371/journal.pone.0036413.g006 results in receptor dimerization. The mifepristone-receptor dimer also binds to hormone response elements and activates some genes as a partial glucocorticoid agonist if glucocorticoid is absent. When both glucocorticoids and mifepristone are present, the mifepris- tone-receptor dimer is transcriptionally inactive as an antagonist of glucocorticoids [35]. Mifepristone binds to the human GR with an affinity 18 times greater than that of cortisol [36]. Because mifepristone blocks the GR in a competitive manner, the effect can be reversed by glucocorticoid administration [37]. The GR, but not the PR, was identified in human uNK cells [17]. Therefore, it is reasonable that the increased cytotoxicity of uNK cells induced by mifepristone is mediated by action at the GR. In addition, the opposite effects due to mifepristone and cortisol on uNK cell- mediated cytotoxicity and perforin expression in the present study indicated that mifepristone acts as an antagonist rather than agonist. NK cells are important for early host defense against infection and tumors [38,39]. They exert cytotoxic effects primarily through granule exocytosis [40,41]. Perforin is a cytolytic mediator that is released by cytoplasmic granules and promotes the death of target cells [42]. Upon release into the immunologic synapse, perforin induces lysis of target cells [43]. Through polymerization and insertion into target cells, perforin causes osmotic leakage and provides access to other toxic granules, which results in lysis and apoptosis of the target cells [44]. NK cell-mediated cytolysis is PLoS ONE | www.plosone.org 7 May 2012 | Volume 7 | Issue 5 | e36413