We have previously shown that NK lineage cells migrate to the murine decidua of pregnancy; but with advancing gestation, they are progressively inactivated in situ by prostaglandins of the E series (PGE2) secreted by decidual cells and decidual macrophages. We have also shown that the same mechanism inactivates all killer lineage cells in the human decidua, and that this inactivation is at least in part due to a down-regulation of IL-2 receptors and an inhibition of IL-2 production in situ. We examined whether chronic indomethacin therapy (to block prostaglandin synthesis), or a systemic administration of a high dose of IL-2, or a combination of both agents administered to pregnant mice could activate killer cells in situ and interfere with the progress of pregnancy; and if so, whether there was a causal relationship between the two events. Pregnant CD1 mice (Day 5 of gestation) were subjected to chronic indomethacin therapy (14 micrograms/ml in drinking water up to Day 15, or 50 micrograms twice daily sc or ip up to Day 10), high dose IL-2 therapy (25,000 Cetus U of human recombinant IL-2, ip every 8 or 12 hr for 3-5 days), or a combination of the two. These treatments led to pregnancy loss in 89-100% of mice, in contrast to 1% loss in control, vehicle-treated mice. Uterine mononuclear cells isolated from the embryo resorption sites exhibited high killer activity against YAC-1 lymphoma as well as murine trophoblast targets, with NK-like phenotype (Asialo GM-1+, Thy-1-) after indomethacin therapy and LAK-like phenotype (AGM-1+, Thy-1+) after IL-2 or indomethacin + IL-2 therapy. That AGM-1+ killer cells resulted in the pregnancy loss was suggested by the findings that in two of three separate experiments, iv injections of AGM-1 ab into pregnant indomethacin + IL-2-treated mice nearly completely prevented the fetoplacental demise (reducing it to 7.7% from 100%). These results reveal that PGE2-mediated inactivation of killer lineage cells in the decidua in situ is conducive to the survival of the conceptus.

译文

我们以前已经证明NK谱系细胞迁移到妊娠的鼠蜕膜; 但是随着妊娠的推进,它们逐渐被蜕膜细胞和蜕膜巨噬细胞分泌的e系列前列腺素 (PGE2) 原位灭活。我们还表明,相同的机制使人蜕膜中的所有杀伤谱系细胞失活,并且这种失活至少部分是由于IL-2受体的下调和原位IL-2产生的抑制。我们检查了慢性吲哚美辛疗法 (阻止前列腺素合成),或全身施用高剂量的IL-2,或两种药物的组合施用给怀孕小鼠是否可以原位激活杀伤细胞并干扰妊娠进程; 如果是这样,这两个事件之间是否存在因果关系。怀孕的CD1小鼠 (妊娠第5天) 接受慢性吲哚美辛治疗 (14微克/毫升饮用水至第15天,或50微克每日两次sc或ip至第10天),高剂量IL-2治疗 (25,000人重组IL-2的鲸鱼座U,ip每8或12小时3-5天),或两者的组合。这些处理导致89-100% 小鼠的妊娠损失,与对照、赋形剂处理的小鼠的1% 损失相反。从胚胎吸收部位分离的子宫单核细胞对YAC-1淋巴瘤和鼠滋养层靶标表现出高杀伤活性,吲哚美辛治疗后具有NK样表型 (Asialo GM-1 +,Thy-1-) 和LAK样表型 (AGM-1 +,thy-1 +) IL-2或吲哚美辛 + IL-2治疗后。AGM-1 + 杀伤细胞导致妊娠损失的研究结果表明,在三个独立实验中的两个实验中,向怀孕的吲哚美辛 + IL-2-treated小鼠静脉注射AGM-1 ab几乎完全阻止了胎儿胎盘的死亡 (将其从100% 减少到7.7%)。这些结果表明,原位蜕膜中杀伤谱系细胞的PGE2-mediated失活有利于概念的存活。

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