Dynamic of interferon signaling and immune regulation in the bovine endometrium during successful and failed pregnancies

The regulation of endometrial-conceptus communication during early pregnancy and its association with pregnancy loss was investigated in beef cattle. Estrous cycles of heifers were synchronized, followed by either a sham procedure (n = 15) or embryo transfer (n = 71) on day 7 (day 1 = ovulation). Endometrial luminal epithelial cells were collected, and luteal function was assessed via Doppler ultrasonography on days 6, 15, and 20. Animals were categorized into five groups (n = 6-8/group): cycling (simulated embryo transfer), EL7-20, EL20-25, EL25-30 (embryo losses detected on days 20, 25, or 30, respectively), and pregnant (confirmed by day 30). Endometrial ISG15 and RSAD2 expression was upregulated in EL20-25, EL25-30, and pregnant groups on days 15 and 20, indicating conceptus-induced immune activation in heifers with maintained corpora lutea. IRF2 was downregulated on day 15 in the EL25-30 and pregnant group. On day 20, IFNγ, IL6, and IL10 were upregulated in EL20-25, EL25-30, and pregnant groups, reflecting immune modulation supportive of pregnancy, whereas IL1β and IL8 were increased only in EL20-25 and EL25-30 groups, indicating a pro-inflammatory state associated with pregnancy loss. TGFβ1 expression increased on day 20 in cycling and EL7-20 groups. TLR2 expression increased between days 6 and 20 in pregnant, EL20-25, and EL25-30 groups, while TLR4 was dysregulated across all groups except pregnant. These findings indicate that the conceptus stimulates early immune activation-characterized by the induction of interferon-stimulated genes, IL6, IL10, IFNγ, and TLR2-by day 15 in recipients with sustained luteal activity, independent of pregnancy outcomes. In contrast, dysregulated IL1β, IL8, and TLR4 expression is associated with early pregnancy failure.