Prostaglandin E₂ is a potent regulator of interleukin‐12‐ and interleukin‐18‐induced natural killer cell interferon‐γ synthesis

Abstract

SUMMARYSynthesis of interferon (IFN)-g by natural killer (NK) cells is an important pro-in¯ammatory 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 in¯ammation this study tested the hypothesis that PGE 2 was capable of directly modulating cytokine-induced NK cell IFN-g synthesis in the absence of other immune cells. Using homogenous NK cell lines to establish direct effects, PGE 2 (0Á1±1 mM) was found to suppress NK cell IFN-g synthesis and antagonized the potent synergistic IFN-g-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-g 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-g 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 ®ndings 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 in¯ammatory processes in vivo through direct suppression of NK cell IFN-g synthesis.

Perioperative Use of β-blockers and COX-2 Inhibitors May Improve Immune Competence and Reduce the Risk of Tumor Metastasis

“…42 Lastly, decreasing excess release of PGs is expected to enhance CMI by shifting the cytokine balance towards Th1 dominance and IFNγ secretion by NK cells. 29 Taken together, administration of COX-2 inhibitors perioperatively could halt tumor progression and enhance immune competence before and after surgery.…”

“…Importantly, whereas none of the blockers alone attenuated the suppression of circulating or pulmonary NKCA, their combined use was markedly effective, indicating synergistic impact of the blockers. This synergism may be attributed to the fact that both CAs and PGs can independently suppress NKCA by activating their respective membrane receptors on NK cells, [27][28][29][30][31] causing intracellular elevation of cAMP levels. 28,32,33 Thus, when both CAs and PGs are in excess, only their simultaneous blockade can prevent NK suppression through this mechanism.…”

Propofol inhibits cyclo-oxygenase activity in human monocytic THP-1 cells

“…[37][38][39][40][41] For example, PGE 2 has been shown to cause immunosuppression by inhibiting LPS-induced interleukin (IL)-12 production by monocytes, decreasing the IL-2-driven proliferation of T cells, and/or suppressing interferon-c production by natural killer cells and T cells. [37][38][39][40][41] Therefore, it is possible that propofol, via inhibition of COX-2 activity and PGE 2 production, mitigates immunosuppression frequently seen in patients during the perioperative period. 4,5 However, these possibilities should be validated in patients undergoing the long-term use of propofol for sedation.…”

The effect of perioperative analgesic drugs omnopon and dexketoprofen on the functional activity of immune cells in murine model of tumor surgery

“…However, on day 3 after the surgery the highest level of splenocytes cytotoxicity retained in animals treated with COX-2 inhibitor dexketoprofen with mean values (62.2 ± 2.4)% against (50.2 ± 3.3)% in omnopon-treated mice and (47.6 ± 1.7)% in control mice (P < 0.02). It has been reported, that PGE 2 suppresses the cytolytic effector functions of NK cells, in a mechanism involving suppression of IL-2, and inhibits production of IFN-γ by NK cells [20]. Furthermore, PGE 2 -mediated suppression of NK cell function during surgery has been shown to facilitate the establishment of metastases in experimental animals [21].…”