Cytochrome P450 26A1 modulates natural killer cells in mouse early pregnancy.
Cytochrome P450 26A1 modulates natural killer cells in mouse early pregnancy.
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细胞色素 P450 26A1 调节小鼠妊娠早期的自然杀伤细胞
DOI：
10.1111/jcmm.13013
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发表时间：
2017-04
影响因子：
5.3
通讯作者：
Peng JP
中科院分区：
文献类型：
--
作者：
Meng CY;Li ZY;Fang WN;Song ZH;Yang DD;Li DD;Yang Y;Peng JP
细胞色素P450 26A1(CYP26A1)在子宫中具有时空表达模式，在围着床期其mRNA和蛋白水平显著升高。抑制细胞色素P26A1的功能或表达可导致妊娠失败，提示细胞色素P26A1在维持妊娠中起着重要的调节作用。然而，人们对其中涉及的确切机制知之甚少。本研究利用pCR3.1-cyp26a1质粒免疫小鼠模型和Cyp26a1-MO(Cyp26a1特异性反义寡核苷酸)基因敲除小鼠模型，观察到pCR3.1-cyp26a1质粒免疫和Cyp26a1-MO处理的小鼠子宫自然杀伤(Unk)细胞数量减少。而在两种模型中，治疗组小鼠子宫中CD3−、CD49b+NK细胞百分率均显著高于对照组。同样，pCR3.1-cyp26a1-和Cyp26a1-MO处理的小鼠子宫中CD49b(一种泛NK细胞标记物)、干扰素-γ、CCL2、CCR2(CCL2受体)和CCL3的表达也显著上调。转录组分析提示，CYP26A1可能通过趋化因子对NK细胞进行调控。结论：沉默细胞色素P26A1的表达/功能可以减少妊娠小鼠子宫中UNK细胞的数量，显著提高CD3−CD49b+NK细胞的百分率。这些发现提供了一条新的证据，将妊娠期间阻断CYP26A1的有害影响与子宫中NK细胞的异常调节联系起来。
Cytochrome P450 26A1 (CYP26A1) has a spatiotemporal expression pattern in the uterus, with a significant increase in mRNA and protein levels during peri‐implantation. Inhibiting the function or expression of CYP26A1 can cause pregnancy failure, suggesting an important regulatory role of CYP26A1 in the maintenance of pregnancy. However, little is known about the exact mechanism involved. In this study, using a pCR3.1‐cyp26a1 plasmid immunization mouse model and a Cyp26a1‐MO (Cyp26a1‐specific antisense oligos) knockdown mouse model, we report that the number of Dolichos biflorus agglutinin (DBA) lectin‐positive uterine natural killer (uNK) cells was reduced in pCR3.1‐cyp26a1 plasmid immunized and Cyp26a1‐MO‐treated mice. In contrast, the percentage of CD3− CD49b+ NK cells in the uteri from the treatment group was significantly higher than that of the control group in both models. Similarly, significantly up‐regulated expression of CD49b (a pan‐NK cell marker), interferon gamma, CCL2, CCR2 (CCL2 receptor) and CCL3 were detected in the uteri of pCR3.1‐cyp26a1‐ and Cyp26a1‐MO‐treated mice. Transcriptome analysis suggested that CYP26A1 might regulate NK cells through chemokines. In conclusion, the present data suggest that silencing CYP26A1 expression/function can decrease the number of uNK cells and significantly increase the percentage of CD3− CD49b+ NK cells in the uteri of pregnant mice. These findings provide a new line of evidence correlating the deleterious effects of blocking CYP26A1 in pregnancy with the aberrant regulation of NK cells in the uterus.