The transcriptional foundations of interferon‐λ‐mediated endometrial cell to uterine receptivity

Abstract Problem 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. Method of study 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. Results 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. Conclusions 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.