目的:干扰素-λ(IFN-λ)是一种新型的非冗余调节因子,参与胎儿-母体免疫相互作用,包括免疫调节,子宫容受性,细胞迁移和粘附,和子宫内膜凋亡。然而,IFN-λ子宫内膜信号的确切转录基础尚未完全了解,关于IFN-λ在体内植入失败的研究是有限的。
方法:使用RNA测序分析用IFN-λ或IFN-α(100ng/mL)处理6小时的人子宫内膜Ishikawa细胞系的基因表达谱。实时qPCR,西方印迹,和酶联免疫吸附测定(ELISA)测试用于验证这些测序数据。进行体内IFN-λ敲低小鼠妊娠模型,并对子宫样本进行表型分析和宫内生物标志物检测。
结果:先前与子宫内膜容受性相关的基因检测到高水平的信使RNA(mRNA),包括LIF,AXL,CRYAB,IFN-λ处理后的EPHB2、CCL5和DDX58。此外,数据表明,与IFN-α相比,IFN-λ降低了促炎基因活性,包括ISG成员,TNF,SP100和白细胞介素基因。体内小鼠妊娠模型表明,抑制宫内IFN-λ会导致上皮表型异常,并显着降低胚胎植入率并破坏正常的子宫容受性。
结论:这些发现证明了IFNs在子宫内膜细胞中的拮抗和激动作用,提示IFN-λ在子宫内膜容受性和免疫耐受调节中的选择性作用。此外,这些研究结果为了解与子宫内膜容受性相关的潜在生物标志物提供了有价值的见解,并有助于了解在不孕症治疗和避孕使用过程中观察到的分子变化.
Interferon-λ (IFN-λ) is a novel non-redundant regulator that participates in the fetal-maternal immune interaction, including immune regulation, uterine receptivity, cell migration and adhesion, and endometrium apoptosis. However, the exact transcriptional foundation for endometrial signaling of IFN-λ is not completely understood, and studies regarding IFN-λ to implantation failure in vivo are limited.
The gene expression profile of human endometrial Ishikawa cell line treated with IFN-λ or IFN-α (100 ng/mL) for 6 h was analyzed using RNA-sequencing. Real-time qPCR, western blotting, and enzyme-linked immunosorbent assay (ELISA) tests were used to validate these sequencing data. An in vivo IFN-λ knock-down mouse pregnancy model was performed, and the phenotype analysis and the intrauterine biomarkers detection were applied with the uterus samples.
High levels of messenger RNA (mRNA) were detected for genes previously associated with endometrial receptivity, including LIF, AXL, CRYAB, EPHB2, CCL5, and DDX58, following IFN-λ treatment. Moreover, the data indicated IFN-λ reduced pro-inflammatory gene activity compared with IFN-α, including members of the ISG, TNF, SP100 and interleukin genes. The in vivo mouse pregnancy model showed that inhibition of intrauterine IFN-λ results in aberrant epithelial phenotype and significantly decreases the embryo implantation rates and derails normal uterine receptivity.
These findings demonstrate the antagonistic and agonistic roles of IFNs in the endometrial cell, suggesting a selective role of IFN-λ in endometrial receptivity and immunological tolerance regulation. Moreover, the findings provide valuable insight into potential biomarkers related to endometrial receptivity and facilitate an understanding of the molecular changes observed during infertility treatment and contraception usage.