Interferon-Tau regulates a plethora of functions in the corpus luteum

Abstract

The corpus luteum (CL) plays a vital role in regulating the reproductive cycle, fertility, and in maintaining pregnancy. Interferon-tau (IFNT) is the maternal recognition of a pregnancy signal in domestic ruminants; its uterine, paracrine actions, which extend the CL lifespan, are widely established. However, considerable evidence also suggests a direct, endocrine role for IFNT. The purpose of this review is to highlight the importance of IFNT in CL maintenance, acting directly and in a cell-specific manner. A transcriptomic study revealed a distinct molecular profile of IFNT-exposed day 18, pregnant bovine CL, compared to the non-pregnant gland. A substantial fraction of the differentially expressed genes was downregulated, many of which are known to be elevated by prostaglandin F2A (PGF2A). In vitro, IFNT was found to mimic changes observed in the luteal transcriptome of early pregnancy. Key luteolytic genes such as endothelin-1 (EDN1), transforming growth factor-B1 (TGFB1), thrombospondins (THBSs) 1&2 and serpine-1 (SERPINE1) were downregulated in luteal endothelial cells. Luteal steroidogenic large cells (LGCs) were also found to be a target for the antilutelotytic actions of IFNT. IFNT-treated LGCs showed a significant reduction in the expression of the proapoptotic, antiangiogenic THBS1&2, as well as TGFBR1 and 2. Furthermore, IFNT was shown to be a potent survival factor for luteal cells in vivo and in vitro, activating diverse pathways to promote cell survival while suppressing cell death signals. Pentraxin 3 (PTX3), robustly upregulated by IFNT in various luteal cell types, mediated many of the prosurvival effects of IFNT in LGCs. A novel reciprocal inhibitory crosstalk between PTX3 and THBS1 lends further support to their respective survival and apoptotic actions in the CL. Even though IFNT did not directly regulate progesterone synthesis, it could maintain its concentrations, by increasing luteal cell survival and by supporting vascular stabilization. The direct effects of IFNT in the CL, enhancing cell survival and vasculature stabilization while curbing luteolytic activities, may constitute an important complementary branch leading to the extension of the luteal lifespan during early pregnancy.

Keywords: Pentraxin-3; Pregnancy; Thrombospondins; cell survival; luteal cells; ruminants.