Interferon-tau regulates the PGE2/PGF2α ratio via ISG15 in the goat corpus luteum during early pregnancy

The corpus luteum (CL) is essential for progesterone production and maintenance of early pregnancy in ruminants. Luteal function is critically influenced by the balance between prostaglandin E₂ (PGE₂) and F_2α (PGF_2α), which is regulated by key synthases such as PTGES and PGFS. Interferon-tau (IFNT), the pregnancy recognition signal in ruminants, is known to modulate prostaglandin production. However, its precise role and underlying mechanisms in regulating PGE₂ and PGF_2α production within goat CL remain unclear. In this study, the expression of key prostaglandin synthases was progressively upregulated in the CL throughout early pregnancy (days 5-18), accompanied by an increase in the PTGES/PGFS ratio. In goat luteal cells, IFNT significantly increased PTGES expression without affecting PGFS, and elevated the PGE₂/PGF_2α ratio. IFNT dose- and time-dependently induced ISG15 expression, and concurrently upregulated ISGylation-related Enzymes. Notably, ISG15 overexpression recapitulated the effects of IFNT by selectively upregulating PTGES expression, thereby enhancing PGE₂ production and the PGE₂/PGF_2α ratio. Conversely, ISG15 knockdown attenuated the IFNT-induced effects. Further mechanistic investigations revealed that both conjugated and free forms of ISG15 contribute to the upregulation of PTGES and the subsequent increase in the PGE₂/PGF_2α ratio. Collectively, these findings identify ISG15-mediated elevation of the PGE₂/PGF_2α ratio as a key mechanism by which the pregnancy recognition signal IFNT protects the CL, providing new insights into the maintenance of early pregnancy in goats.