Prostaglandin E2 Suppressed IL-15-Mediated Human NK Cell Function Through Down-Regulation of Common γ-Chain

NK cell function is regulated by cytokines and certain biochemical mediators in a positive or negative manner. This study was performed to investigate the suppressive effects of PGE(2) on IL-15-activated human NK cell function. Purified NK cells were cultured with 200 ng/ml IL-15 for 2 days in the presence or absence of 10-200 ng/ml PGE(2). PGE(2) significantly suppressed NK cell-mediated cytotoxicity and IFN-gamma production at the secretional and the transcriptional levels. We also evaluated the effect of PGE(2) on the IL-15R complex that consists of IL-2Rbeta, common gamma-chain (gamma(c)-chain), and a specific chain IL-15Ralpha. Percentage of positive cells and number of binding sites for gamma(c)-chain were significantly increased after IL-15 treatment; however, a substantial decrease was observed with PGE(2) cotreatment. In contrast, constitutive expression of IL-2Rbeta was significantly decreased after IL-15 treatment, with no change detected in the presence of PGE(2.) At the transcriptional level, neither IL-15 nor PGE(2) had significant effects on the expression of beta- or gamma(c)-chains. There was a 3-fold increase in the expression of IL-15Ralpha at the transcriptional level that peaked at 8 h after IL-15 treatment; however, PGE(2) had no significant effect. Suppression of NK function by PGE(2) was not due to the endogenous production of IL-4, IL-10, or TGF-beta(1) by NK cells. These results suggest that down-regulation of surface expression of gamma(c)-chain on NK cells may be one mechanism through which PGE(2) mediates suppression of IL-15-activated NK cell function.