Li Z-Y, Chao H-H, Liu H-Y, Song Z-H, Li L-L, Zhang Y-J, Yang Y, Peng J-P
1] State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China [2] University of Chinese Academy of Sciences, Beijing, People's Republic of China.
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China.
Cell Death Dis. 2014 Nov 6;5(11):e1512. doi: 10.1038/cddis.2014.470.
Interferon-γ (IFN-γ), a pleiotropic lymphokine, has important regulatory effects on many cell types. Although IFN-γ is essential for the initiation of uterine vascular modifications and maintenance of decidual integrity, IFN-γ administration can also cause pregnancy failure in many species. However, little is known about the effector mechanisms involved. In this study, using an IFN-γ-induced abortion mouse model, we reported that no Dolichos biflorus agglutinin lectin-positive uterine natural killer (uNK) cells were observed in the uteri from IFN-γ-induced abortion mice. By contrast, the percentage of CD3(-)CD49b(+) NK cells in the uterus and blood from a foetal resorption group was significantly higher than that of the control group. Similarly, significantly upregulated expression of CD49b (a pan-NK cell marker), CX3CL1 and CX3CR1 (CX3CL1 receptor) was detected in the uteri of IFN-γ-induced abortion mice. Using isolated uterine stromal cells, we showed that upregulated expression of CX3CL1 by IFN-γ was dependent on a Janus family kinase 2-signal transducers and activators of transcription 1 (JAK2-STAT1) pathway. We further demonstrated the chemotactic activity of CX3CL1 in uterine stromal cell conditioned medium on primary splenic NK cells. Finally, we observed increased recruitment of CD49b(+) NK cells into the endometrium after exogenous CX3CL1 administration. Collectively, our findings indicate that IFN-γ can significantly increase uterine CX3CL1 expression via activation of the JAK2-STAT1 pathway, thus inducing CD49b(+) NK cell uterine homing, and eventually provoke foetal loss. Thus, we provide a new line of evidence correlating the deleterious effects of IFN-γ on pregnancy with the aberrant regulation of CX3CL1 and CD49b(+) NK cells.
γ干扰素（IFN-γ）是一种多效性淋巴因子，对多种细胞类型具有重要的调节作用。尽管IFN-γ对于启动子宫血管改变和维持蜕膜完整性至关重要，但在许多物种中，给予IFN-γ也会导致妊娠失败。然而，对于其中涉及的效应机制却知之甚少。在本研究中，我们使用IFN-γ诱导流产的小鼠模型，报告称在IFN-γ诱导流产小鼠的子宫中未观察到双花扁豆凝集素阳性的子宫自然杀伤（uNK）细胞。相比之下，胎儿吸收组子宫和血液中CD3(-)CD49b(+) NK细胞的百分比显著高于对照组。同样，在IFN-γ诱导流产小鼠的子宫中检测到CD49b（一种泛NK细胞标志物）、CX3CL1和CX3CR1（CX3CL1受体）的表达显著上调。使用分离的子宫基质细胞，我们表明IFN-γ对CX3CL1表达的上调依赖于Janus家族激酶2-信号转导子和转录激活子1（JAK2-STAT1）途径。我们进一步证明了子宫基质细胞条件培养基中的CX3CL1对原代脾NK细胞具有趋化活性。最后，我们观察到外源性给予CX3CL1后，CD49b(+) NK细胞向子宫内膜的募集增加。总体而言，我们的研究结果表明，IFN-γ可通过激活JAK2-STAT1途径显著增加子宫CX3CL1表达，从而诱导CD49b(+) NK细胞归巢至子宫，最终导致胎儿丢失。因此，我们提供了一系列新的证据，将IFN-γ对妊娠的有害影响与CX3CL1和CD49b(+) NK细胞的异常调节联系起来。
