Novel mechanisms induced by pregnancy recognition signal interferon-tau to maintain corpus luteum function

The corpus luteum (CL) is a transient endocrine gland, its progesterone secretion is essential for establishment and maintenance of pregnancy in mammalian species. In domestic ruminants, embryonically derived interferon-tau (IFNT) maintains the CL function, it is released into the uterine vein and might act as an endocrine hormone. Thus, we investigated whether IFNT directly affects the function of large luteal–like cells (LLCs), a major contributor to progesterone output from the CL. We found that IFNT acts through type-1 interferon pathway by phosphorylating STAT1 and elevating IFN-stimulated genes (ISGs; MX2, ISG15, and OAS1Y) in LLCs. Importantly, IFNT increased viable LLC numbers and decreased FACS-sorted apoptotic/dead cell counts. IFNT treatment elevated BIRC5 encoding survivin and decreased FASL. Consistent with these findings, IFNT upregulated LLCs survival proteins (MCL1, BCL-xL, and XIAP) while reducing the levels of proteins implicated in cell death (gamma-H2AX, cleaved caspase-3, and thrombospondin; THBS). Furthermore, IFNT reversed the pro-apoptotic actions of THBS1 on LLCs. We also noted that IFNT markedly stimulated pentraxin-3 in LLCs and CL slices. Pentraxin-3 was shown to play crucial roles in remodeling cumulus ECM in preparation for ovulation. Silencing pentraxin-3 in LLCs with specific siRNA, decreased IFNT-induced viable cells and reversed IFNT-dependent effects on the FASL and BIRC5. Moreover, pentraxin-3 ablation also reduced apoptotic THBS1 expression and function. Together, this study reveals that IFNT is a survival factor for luteal cells. Acting via various mechanisms such as counteracting THBS-mediated apoptotic activities and elevating pentraxin-3, IFNT may contribute to CL maintenance, thus supporting early pregnancy.