Zhang J H, He H, Borzychowski A M, Takeda K, Akira S, Croy B A
Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
Biol Reprod. 2003 Aug;69(2):404-11. doi: 10.1095/biolreprod.103.015529. Epub 2003 Mar 19.
In mice and women, terminal differentiation of uterine natural killer (uNK) cells commences during endometrial decidualization. Both proliferation and interferon (IFN)-gamma are induced. Uterine NK cell precursors appear to home from secondary lymphoid organs to decidualizing uteri and localize mesometrially to the central decidua basalis, the site of maternal arterial modification at Gestation Days (gd) 9.5-10. In mice, genetic absence of uNK cells results in absence of pregnancy-induced spiral artery modification. Administration of IFN-gamma to uNK-negative pregnant females induces arterial modifications without fetal loss. In this study, we investigated the roles of cytokines, known in other tissues to differentiate and activate NK cells, in induction of IFN-gamma production in normal mouse implantation sites. Fecundity evaluation, implantation site morphometry, and IFN-gamma quantification in interleukin (IL)-12p40(0/0), IL-18(0/0), dual IL-12p40(0/0)/IL-18(0/0) and congenic strains revealed the importance of both IL-12 and IL-18 in the induction of spiral artery modification and IFN-gamma synthesis. Immediately after implantation, IL-18 was localized transiently to decidual cells, but by gd8, IL-18 was produced solely by uNK cells, suggesting that early uNK cells are activated by stroma and lymphocyte-derived signals maintain later uNK cell activation. Mesometrial tissue of C57Bl/6J mice was examined by reverse transcription polymerase chain reaction assay in virgin, early postimplantation, and midgestation females for expression of the heterodimeric cytokines IL-23 (composed of IL-12p40 and a novel alpha chain), IL-27 (composed of two IL-12-related chains) and IL-27R. No expression was detected in virgin uteri. The four genes were induced by gd6, and uNK cells isolated from midgestation transcribed IL-23alpha and IL-27R. This study advances the understanding of uNK cell activation during normal pregnancy.
在小鼠和女性中，子宫自然杀伤（uNK）细胞的终末分化在子宫内膜蜕膜化过程中开始。增殖和干扰素（IFN）-γ均被诱导。子宫NK细胞前体似乎从次级淋巴器官归巢至正在蜕膜化的子宫，并在子宫系膜侧定位于中央基蜕膜，即妊娠第9.5 - 10天母体动脉发生改变的部位。在小鼠中，uNK细胞基因缺失导致妊娠诱导的螺旋动脉改变缺失。给uNK细胞阴性的怀孕雌性小鼠注射IFN-γ可诱导动脉改变且不导致胎儿丢失。在本研究中，我们调查了在其他组织中已知可分化和激活NK细胞的细胞因子在正常小鼠着床部位诱导IFN-γ产生中的作用。对白细胞介素（IL）-12p40(0/0)、IL-18(0/0)、双敲除IL-12p40(0/0)/IL-18(0/0)小鼠及同基因品系进行生育力评估、着床部位形态测量和IFN-γ定量分析，揭示了IL-12和IL-18在诱导螺旋动脉改变和IFN-γ合成中的重要性。着床后即刻，IL-18短暂定位于蜕膜细胞，但到妊娠第8天，IL-18仅由uNK细胞产生，这表明早期uNK细胞由基质激活，而淋巴细胞衍生的信号维持后期uNK细胞的激活。通过逆转录聚合酶链反应分析检测C57Bl/6J小鼠在未交配、着床早期和妊娠中期子宫系膜组织中异二聚体细胞因子IL-23（由IL-12p40和一条新的α链组成）、IL-27（由两条与IL-12相关的链组成）及IL-27R的表达。在未交配的子宫中未检测到表达。这四个基因在妊娠第6天被诱导，从妊娠中期分离的uNK细胞转录IL-23α和IL-27R。本研究增进了对正常妊娠期间uNK细胞激活的理解。
