Walker William, Rotondo Dino
Experimental Medicine Unit, Swansea Clinical School, University of Wales-Swansea, Swansea SA2 8PP, Wales, UK.
Immunology. 2004 Mar;111(3):298-305. doi: 10.1111/j.1365-2567.2004.01810.x.
Synthesis of interferon (IFN)-gamma 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 E2 (PGE2) is ubiquitous during inflammation this study tested the hypothesis that PGE2 was capable of directly modulating cytokine-induced NK cell IFN-gamma synthesis in the absence of other immune cells. Using homogeneous NK cell lines to establish direct effects, PGE2 (0.1-1 micro m) was found to suppress NK cell IFN-gamma synthesis and antagonized the potent synergistic IFN-gamma-inducing effects of IL-12 and IL-18. The actions of PGE2 were mimicked by synthetic PGE2 analogues including misoprostol and butaprost. The selective EP2 receptor agonist butaprost, but not the EP1/EP3 agonist sulprostone, suppressed IFN-gamma synthesis and exclusively competed with PGE2 for receptor binding on NK cells. Further analysis showed that PGE2 did not modulate IL-12 receptor mRNA expression and the effects of PGE2 could be mimicked by the phosphodiesterase inhibitor 3-iosobutyl-1-methylxanthine. The absence of demonstrable receptor modulation coupled with the observed suppression of IFN-gamma synthesis by both EP2 receptor-selective agonists and IBMX suggest that PGE2 acts directly on NK cells via EP2 receptors with its downstream effects on cAMP metabolism. This conclusion is further supported by findings that PGE2 and its analogues consistently elevated levels of cAMP in NK cells. The ability of PGE2 to antagonize the potent inductive signal provided by the combination of IL-12 and IL-18 supports the concept that PGE2 may play an important role in limiting innate inflammatory processes in vivo through direct suppression of NK cell IFN-gamma synthesis.
自然杀伤（NK）细胞合成干扰素（IFN）-γ是一个重要的促炎事件，白细胞介素（IL）-12和IL-18在其中发挥主要诱导作用。然而，其他时间性事件可能会调节此类过程，并且由于前列腺素E2（PGE2）在炎症过程中普遍存在，本研究检验了以下假设：在没有其他免疫细胞的情况下，PGE2能够直接调节细胞因子诱导的NK细胞IFN-γ合成。使用同源NK细胞系来确定直接作用，发现PGE2（0.1 - 1微摩尔）可抑制NK细胞IFN-γ合成，并拮抗IL-12和IL-18强大的协同IFN-γ诱导作用。合成的PGE2类似物包括米索前列醇和布他前列素可模拟PGE2的作用。选择性EP2受体激动剂布他前列素，而非EP1/EP3激动剂舒前列素，可抑制IFN-γ合成，并专门与PGE2竞争NK细胞上的受体结合。进一步分析表明，PGE2不调节IL-12受体mRNA表达，并且磷酸二酯酶抑制剂3-异丁基-1-甲基黄嘌呤可模拟PGE2的作用。未观察到明显的受体调节，同时EP2受体选择性激动剂和异丁基甲基黄嘌呤均观察到对IFN-γ合成的抑制，这表明PGE2通过EP2受体直接作用于NK细胞，对环磷酸腺苷（cAMP）代谢产生下游影响。PGE2及其类似物可使NK细胞中的cAMP水平持续升高，这一发现进一步支持了该结论。PGE2拮抗IL-12和IL-18组合提供的强大诱导信号的能力支持了这样一种观点，即PGE2可能通过直接抑制NK细胞IFN-γ合成在体内限制先天性炎症过程中发挥重要作用。
