Uterine Vein Infusion of Interferon Tau (IFNT) Stimulates Luteal Gene Expression, Prevents Anti-Steroidogenic Actions of Prostaglandin F2alpha (PGF) and Extends Luteal Lifespan in Ewes.

Interferon-tau (IFNT) from the ovine conceptus has paracrine actions on the endometrium which alter release of prostaglandin F2α (PGF) and protect the corpus luteum (CL). Until recently, conceptus-derived IFNT was thought to act primarily within the uterus. We previously demonstrated greater antiviral activity in uterine vein blood and expression of interferon stimulated genes (ISGs, i.e., ISG15) in blood and CL in pregnant vs. non-pregnant ewes. Therefore, we hypothesized that IFNT contributes to antiviral activity in uterine vein blood and has endocrine actions on the CL. Blood serum and plasma from uterine vein of Day 15 pregnant ewes were pre-adsorbed with antisera raised against recombinant ovine (ro)IFNT or with normal rabbit serum. Antiviral index in blood samples pre-adsorbed with antisera against IFNT was reduced compared to samples pre-adsorbed with normal rabbit serum (P<0.05) and did not differ from antiviral index in blood from non-pregnant ewes. Hence, the antiviral activity in blood from uterine vein of Day 15 pregnant ewes is due to IFNT. Infusion, by using mini-osmotic pumps of 200 μg roIFNT (2 X 10⁷ antiviral units) over 24 h into the uterine vein induced greater (P<0.05) expression of ISG15 in the CL on Day 10 of the estrous cycle than injection of 200 μg roIFNT over 2 min into the uterine artery. Endocrine action of IFNT was further examined through infusion of roIFNT or BSA (200 μg/24 h; mini-osmotic pump; n=12 ewes/group) into the uterine vein of non-pregnant ewes from Days 10 to 11 post-estrus. ISG15 mRNA and protein were more abundant in CL following 24 h roIFNT infusion compared to BSA infusion (P<0.05). Injection of subluteolytic PGF (5 mg; n=6 ewes/group) at 12 h following insertion of the pumps caused a decline in serum progesterone (P4) at 6 h and a further decline at 12 h in BSA-infused ewes (P<0.05). Ewes infused with roIFNT responded to PGF with a similar decline in concentrations of serum P4 at 6 h, but then exhibited recovery of serum P4 to levels similar to control ewes at 12 h. Because IFNT was shown to be released from the uterus into the uterine vein in pregnant ewes to stimulate ISGs in the CL, and appeared to prevent anti-steroidogenic actions of PGF, we hypothesized that uterine vein infusion of roIFNT would delay the onset of estrus in cyclic ewes. Recombinant oIFNT (n=5 ewes) or BSA (n=6 ewes) was infused (200 μg/day) into the uterine vein for 7 days beginning on Day 10 of the estrous cycle. All BSA-infused ewes returned to estrus by Day 19. One roIFNT-treated ewe returned to estrus by Day 19, but had a more rapid decline in P4 compared to BSA-infused ewes, which suggests that she was exposed to endogenous PGF prior to IFN- or BSA-infused ewes. The other roIFNT-infused ewes did not return to estrus and concentrations of P4 in their serum remained elevated through Day 32 post-estrus. It is concluded that IFNT is released into the uterine vein and acts through an endocrine mechanism to induce luteal expression of ISG15 and prevent anti-luteolytic actions of PGF. Infusion of roIFNT outside the uterus prevents luteolysis of the CL as evidenced by their continued secretion of P4 through 32 days. Further investigation is necessary to fully elucidate endocrine mechanisms involved in IFNT mediation of luteal function and maternal recognition of pregnancy. Research was funded by NRI-USDA-CSREES 2006-35203-17258 and a grant from the Colorado Experiment Station.

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