Prostaglandin E 2 is a potent regulator of interleukin‐12‐ and interleukin‐18‐induced natural killer cell interferon‐γ synthesis

Summary Synthesis of interferon (IFN)‐γ by natural killer (NK) cells is an important pro‐inflammatory event with interleukin (IL)‐12 and IL‐18 playing major inductive roles. However, other temporal events are likely to regulate such processes and as prostaglandin E 2 (PGE 2 ) is ubiquitous during inflammation this study tested the hypothesis that PGE 2 was capable of directly modulating cytokine‐induced NK cell IFN‐γ synthesis in the absence of other immune cells. Using homogenous NK cell lines to establish direct effects, PGE 2 (0·1–1 µ m ) was found to suppress NK cell IFN‐γ synthesis and antagonized the potent synergistic IFN‐γ‐inducing effects of IL‐12 and IL‐18. The actions of PGE 2 were mimicked by synthetic PGE 2 analogues including misoprostol and butaprost. The selective EP 2 receptor agonist butaprost, but not the EP 1 /EP 3 agonist sulprostone, suppressed IFN‐γ synthesis and exclusively competed with PGE 2 for receptor binding on NK cells. Further analysis showed that PGE 2 did not modulate IL‐12 receptor mRNA expression and the effects of PGE 2 could be mimicked by the phosphodiesterase inhibitor 3‐iosobutyl‐1‐methylxanthine. The absence of demonstrable receptor modulation coupled with the observed suppression of IFN‐γ synthesis by both EP 2 receptor‐selective agonists and IBMX suggest that PGE 2 acts directly on NK cells via EP 2 receptors with its downstream effects on cAMP metabolism. This conclusion is further supported by findings that PGE 2 and its analogues consistently elevated levels of cAMP in NK cells. The ability of PGE 2 to antagonize the potent inductive signal provided by the combination of IL‐12 and IL‐18 supports the concept that PGE 2 may play an important role in limiting innate inflammatory processes in vivo through direct suppression of NK cell IFN‐γ synthesis.