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

Abstract

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 PGE2 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 PGE2. PGE2 significantly suppressed NK cell-mediated cytotoxicity and IFN-γ production at the secretional and the transcriptional levels. We also evaluated the effect of PGE2 on the IL-15R complex that consists of IL-2Rβ, common γ-chain (γc-chain), and a specific chain IL-15Rα. Percentage of positive cells and number of binding sites for γc-chain were significantly increased after IL-15 treatment; however, a substantial decrease was observed with PGE2 cotreatment. In contrast, constitutive expression of IL-2Rβ was significantly decreased after IL-15 treatment, with no change detected in the presence of PGE2. At the transcriptional level, neither IL-15 nor PGE2 had significant effects on the expression of β- or γc-chains. There was a 3-fold increase in the expression of IL-15Rα at the transcriptional level that peaked at 8 h after IL-15 treatment; however, PGE2 had no significant effect. Suppression of NK function by PGE2 was not due to the endogenous production of IL-4, IL-10, or TGF-β1 by NK cells. These results suggest that down-regulation of surface expression of γc-chain on NK cells may be one mechanism through which PGE2 mediates suppression of IL-15-activated NK cell function.