Parturition Research Group, Department of Surgery and Cancer, Institute of Reproduction and Developmental Biology, Imperial College London, W120NN London, UK.
Mediators Inflamm. 2012;2012:416739. doi: 10.1155/2012/416739. Epub 2012 May 29.
Pregnancy is a complex immunological state in which a bias towards T helper 2 (Th2) protects the fetus. Evidence suggests that proinflammatory cytokines increase the risk of poor neonatal outcome, independently of the direct effect of preterm labour. The anti-inflammatory prostaglandin 15-deoxy-Δ(12,14)-Prostaglandin J(2) (15dPGJ(2)) inhibits nuclear factor Kappa B (NF-κB) in amniocytes and myocytes in vitro and is a ligand for the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptor. Here we examine the Th1:Th2 cytokine bias in pregnancy and whether 15dPGJ(2) could be used to inhibit the production of the proinflammatory cytokines through inhibition of NF-κB while simultaneously promoting Th2 interleukin 4 (IL-4) synthesis via CRTH2 in T helper cells. Peripheral blood mononuclear cells (PBMCs) from women at 28 weeks, term pre-labour, term labour as well as non-pregnant female controls were cultured with 15dPGJ(2) or vehicle control and stimulated with phorbol myristyl acetate (PMA)/ionomycin. The percentage of CD4(+) cells producing interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) in response to PMA/ionomycin was significantly reduced in pregnancy. 15dPGJ(2) reduced IFN-γ and TNF-α production in stimulated T helper cells, but did not alter IL-4 production in CRTH2(+ve) cells. 15dPGJ(2) also reduced phospho-p65 in stimulated PBMCs. In summary, 15dPGJ(2) suppresses the Th1 response of PBMCs during pregnancy and active labour whilst maintaining the Th2 response suggesting a therapeutic benefit in reducing neonatal morbidity in inflammation-induced PTL.
妊娠是一种复杂的免疫状态，其中偏向辅助性 T 细胞 2（Th2）的免疫反应有利于保护胎儿。有证据表明，促炎细胞因子增加了新生儿不良结局的风险，这与早产的直接影响无关。抗炎性前列腺素 15-脱氧-Δ（12,14）-前列腺素 J2（15dPGJ2）在体外抑制羊水细胞和肌细胞中的核因子 Kappa B（NF-κB），并且是对 Th2 细胞趋化因子受体同源分子（CRTH2）受体有吸引力的配体。在这里，我们检查了妊娠期间的 Th1：Th2 细胞因子偏倚，以及 15dPGJ2 是否可以通过抑制 NF-κB 来抑制促炎细胞因子的产生，同时通过 CRTH2 促进 T 辅助细胞中的 Th2 白细胞介素 4（IL-4）合成。从 28 周、足月前、足月分娩的孕妇和未怀孕的女性对照者的外周血单核细胞（PBMC）中分离出细胞，用 15dPGJ2 或载体对照物培养，并与佛波醇肉豆蔻酸酯（PMA）/离子霉素刺激。对 PMA/离子霉素的反应中，CD4+细胞产生干扰素γ（IFN-γ）和肿瘤坏死因子α（TNF-α）的百分比在妊娠期间显著降低。15dPGJ2 降低了刺激 T 辅助细胞中 IFN-γ 和 TNF-α 的产生，但未改变 CRTH2（+ve）细胞中 IL-4 的产生。15dPGJ2 还降低了刺激 PBMC 中的磷酸化 p65。总之，15dPGJ2 在妊娠和活跃分娩期间抑制 PBMC 的 Th1 反应，同时维持 Th2 反应，提示在减少炎症诱导的 PTL 中新生儿发病率方面具有治疗益处。
