Downregulated luteolytic pathways in the transcriptome of early pregnancy bovine corpus luteum are mimicked by interferon-tau in vitro

Abstract Background Maintenance of the corpus luteum (CL) beyond the time of luteolysis is essential for establishing pregnancy. Identifying the distinct features of early pregnancy CL remains unresolved, hence we analyzed here the transcriptome of CL on day 18 pregnant (P) and non-pregnant (NP) cows using RNA-Seq. CL of P cows expressed ISGs, verifying exposure to the pregnancy recognition signal, interferon-tau (IFNT), whereas the CL of NP cows had elevated luteal progesterone levels, implying that luteolysis had not yet commenced. Results The DEGs, IPA, and metascape canonical pathways, along with GSEA analysis, differed markedly in the CL of P cows from those of NP cows, at the same day of the cycle. Both metascape and IPA identified similar significantly enriched pathways such as interferon alpha/beta, sonic hedgehog pathway, TNFA, EDN1, TGFB1, and PDGF. However, type-1 interferon and sonic hedgehog pathways were positively enriched whereas most of the enriched pathways were downregulated in the P compared to NP samples. Thirty-four % of these pathways are known to be elevated by PGF2A during luteolysis. Notably, selective DEGs in luteinized granulosa cells were modulated by IFNT in vitro in a similar manner to their regulation in the CL of P cows. Conclusion This study unraveled the unique transcriptomic signature of the IFNT-exposed, early pregnancy CL, highlighting the abundance of downregulated pathways known to be otherwise induced during luteolysis. These and IFNT-regulated in vitro pregnancy-specific DEGs suggest that IFNT contributes to the characteristics and maintenance of early pregnancy CL.

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Possible role of interferon tau on the bovine corpus luteum and neutrophils during the early pregnancy

Reproduction ◽

10.1530/rep-15-0085 ◽

2015 ◽

Vol 150 (3) ◽

pp. 217-225 ◽

Cited By ~ 35

Author(s):

Koumei Shirasuna ◽

Haruka Matsumoto ◽

Shuichi Matsuyama ◽

Koji Kimura ◽

Heinrich Bollwein ◽

...

Keyword(s):

Corpus Luteum ◽

Neutrophil Migration ◽

Peripheral Circulation ◽

Interferon Tau ◽

Bovine Corpus Luteum ◽

Activated Neutrophils ◽

Endocrine Factor ◽

Uterine Environment ◽

And Function

When pregnancy is established, interferon tau (IFNT), a well-known pregnancy recognition signal in ruminants, is secreted by embryonic trophoblast cells and acts within the uterus to prepare for pregnancy. IFNT acts as an endocrine factor on the corpus luteum (CL) to induce refractory ability against the luteolytic action of PGF2α. Hypothesising that IFNT may influence not only the uterine environment but also the CL in cows via local or peripheral circulation, we investigated qualitative changes in the CL of pregnant cows during the maternal recognition period (day 16) and the CL of non-pregnant cows. The CL of pregnant animals had a higher number of neutrophils, and the expression of interleukin 8 (IL8) mRNA and its protein was higher as well as compared with the CL of non-pregnant animals. Although IFNT did not affect progesterone (P4) secretion and neutrophil migration directly, it stimulated IL8 mRNA expression on luteal cells (LCs), influencing the neutrophils, resulting in the increased migration of IFNT-activated neutrophils. Moreover, both IFNT-activated neutrophils and IL8 increased P4 secretion from LCs in vitro. Our novel finding was the increase in neutrophils and IL8 within the CL of pregnant cows, suggesting the involvement of IFNT function within the CL toward establishment of pregnancy in cows. The present results suggest that IFNT upregulates neutrophil numbers and function via IL8 on LCs in the CL of early pregnant cows and that both neutrophils and IL8, stimulated by IFNT, are associated with an increase in P4 concentrations during the maternal recognition period in cows.

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Possible involvement of IFNT in lymphangiogenesis in the corpus luteum during the maternal recognition period in the cow

Reproduction ◽

10.1530/rep-11-0157 ◽

2011 ◽

Vol 142 (6) ◽

pp. 879-892 ◽

Cited By ~ 37

Author(s):

Akane Nitta ◽

Koumei Shirasuna ◽

Shingo Haneda ◽

Motozumi Matsui ◽

Takashi Shimizu ◽

...

Keyword(s):

Mrna Expression ◽

Corpus Luteum ◽

Early Pregnancy ◽

Lymphatic System ◽

Lymphatic Vessels ◽

Lymphatic Endothelial Cell ◽

Circulation System ◽

Interferon Tau ◽

Factor C

The corpus luteum (CL), which secretes large amounts of progesterone and is thus essential for establishing pregnancy, contains various types of immune cells that may play essential roles in CL function by generating immune responses. The lymphatic system is the second circulation system and is necessary for immune function, but the lymphatic system of the bovine CL has not been characterized in detail. We collected bovine CLs on days 12 and 16 of the estrous cycle (C12 and C16) and days 16 and 40 of early pregnancy (P16 and P40). Lymphatic endothelial hyaluronan receptor 1 (LYVE1) protein was detected in the CL by immunohistochemistry and western blotting and increased at P40 compared with C16. The mRNA expression levels of lymphangiogenic factors, such as vascular endothelial growth factor-C (VEGFC),VEGFD, and their common receptorVEGFR3, as well as the lymphatic endothelial cell (LyEC) marker podoplanin, increased in P16 and P40 CLs. Thus, it is suggested that the lymphatic system of the bovine CL reconstitutes during early pregnancy. Interferon tau (IFNT) from the conceptus in the uterus is a candidate for activating luteal lymphangiogenesis during the maternal recognition period (MRP). We found that treatment of LyECs isolated from internal iliac lymphatic vessels with IFNT stimulated LyEC proliferation and significantly increased mRNA expression ofVEGFCand IFN-stimulated gene 15. Moreover, both IFNT and VEGFC induced LyECs to form capillary-like tubesin vitro. In conclusion, it is suggested that new lymphangiogenesis in the bovine CL begins during the MRP and that IFNT may mediate this novel phenomenon.

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Biosynthesis of Progesterone, Sterols, and Squalene from Acetate-1-14C and Mevalonate-2-14C by the Bovine Corpus Luteum in Vitro

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)97410-7 ◽

1965 ◽

Vol 240 (5) ◽

pp. 1957-1961

Author(s):

Hermione R. Hellig ◽

Kenneth Savard

Keyword(s):

Corpus Luteum ◽

Bovine Corpus Luteum

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In Vitro Production of Angiotropic Factor by Bovine Corpus Luteum: Partial Characterization of Activities that are Chemotactic and Mitogenic for Endometrial Cells

Advances in Experimental Medicine and Biology - Regulation of Ovarian and Testicular Function ◽

10.1007/978-1-4684-5395-9_42 ◽

1987 ◽

pp. 683-688 ◽

Cited By ~ 8

Author(s):

D. A. Redmer ◽

J. D. Kirsch ◽

A. T. Grazul

Keyword(s):

Corpus Luteum ◽

Partial Characterization ◽

In Vitro Production ◽

Endometrial Cells ◽

Bovine Corpus Luteum ◽

Vitro Production

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Control of Steroidogenesis in Small and Large Bovine Luteal. Cells

Australian Journal of Biological Sciences ◽

10.1071/bi9870331 ◽

1987 ◽

Vol 40 (3) ◽

pp. 331 ◽

Cited By ~ 45

Author(s):

William Hansel ◽

Hector W Alila ◽

Joseph P Dowd ◽

Xiangzhong Yang

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Corpus Luteum ◽

Luteal Cell ◽

Lipoxygenase Pathway ◽

Luteal Cells ◽

Kinase C ◽

Bovine Corpus Luteum ◽

Progesterone Synthesis

Evidence was cited to show that: (1) prostacyclin (PGI2) plays a luteotrophic role in the bovine corpus luteum and that products of the lipoxygenase pathway of arachidonic acid metabolism, especially 5-hydroxyeicosatetraenoic acid play luteolytic roles; (2) oxytocin of luteal cell origin plays a role in development, and possibly in regression, of the bovine corpus luteum; and (3) luteal cells arise from two sources; the characteristic small luteal cells at all stages of the o~strous cycle and pregnancy are of theca cell origin; the large cells are of granulosa cell origin early in the cycle, but a population of theca-derived large cells appears later in the cycle. Results of in vitro studies with total dispersed cells and essentially pure preparations of large and small luteal cells indicate that : (1) the recently described Ca2+ -polyphosphoinositol-protein kinase C second messenger system is involved in progesterone synthesis in the bovine corpus luteum; (2) activation of protein kinase C is stimulatory to progesterone synthesis in the small luteal cells; (3) activation of protein kinase C has no effect on progesterone synthesis in the large luteal cells; and (4) protein kinase C exerts its luteotrophic effect in total cell preparations, in part at least, by stimulating the production of prostacyclin. The protein kinase C system may cause down regulation of LH receptors in the large cells.

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Blood perfusion and diameter of bovine corpus luteum as predictors of luteal function in early pregnancy

Reproduction in Domestic Animals ◽

10.1111/rda.14046 ◽

2021 ◽

Author(s):

Gabriella dos Santos Velho ◽

Monique Tomazele Rovani ◽

Rogério Ferreira ◽

Bernardo Garziera Gasperin ◽

André Gustavo Cabrera Dalto

Keyword(s):

Corpus Luteum ◽

Early Pregnancy ◽

Blood Perfusion ◽

Luteal Function ◽

Bovine Corpus Luteum

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109 EFFECT OF SHORT TERM PROGESTERONE SUPPLEMENTATION ON CIRCULATING PROGESTERONE CONCENTRATION, CORPUS LUTEUM SIZE, AND EARLY EMBRYO DEVELOPMENT IN CATTLE

Reproduction Fertility and Development ◽

10.1071/rdv25n1ab109 ◽

2013 ◽

Vol 25 (1) ◽

pp. 202

Author(s):

L. O'Hara ◽

N. Forde ◽

D. Rizos ◽

V. Maillo ◽

A. D. Ealy ◽

...

Keyword(s):

Corpus Luteum ◽

Early Embryo ◽

Negative Effects ◽

Short Term ◽

Concentration Data ◽

Interferon Tau ◽

Fluid Medium ◽

Conceptus Development ◽

Oviduct Fluid

The aim of this study was to investigate the effect of short term progesterone (P4) supplementation on circulating P4 concentrations, corpus luteum (CL) size, and conceptus development in cattle. The oestrous cycles of crossbred beef heifers were synchronised using a 7-day PRID® Delta (1.55 g P4) treatment with administration of a PGF2α analog (Enzaprost®) the day before PRID® Delta removal. Only those recorded in standing oestrus (Day 0) were used. In Experiment 1, heifers were randomly assigned to 1 of 5 groups: (1) control: no treatment, (2) placebo: insertion of a blank device (no P4) from Day 3 to 7, (3) insertion of a PRID® Delta from Day 3 to 7, (4) insertion of a PRID® Delta from Day 3 to 5, or (v5) insertion of a PRID® Delta from Day 5 to 7. In vitro produced blastocysts were transferred to each heifer on Day 7 (10 blastocysts per heifer) and conceptuses were recovered at slaughter on Day 14. In Experiment 2 heifers were artificially inseminated at oestrus and randomly assigned to 1 of 3 treatment groups (1) placebo, (2) PRID® Delta from Day 3 to 5, or (3) PRID® Delta from Day 3 to 7. All heifers were slaughtered on Day 16, and recovered conceptuses were incubated in synthetic oviduct fluid medium for 24 h; spent media and uterine flushes were analysed for interferon-tau (IFNT). In both experiments, daily blood samples were taken to measure serum P4 concentration. Data were analysed using the PROC MIXED procedure of SAS (SAS Institute Inc., Cary, NC, USA). Insertion of a PRID® Delta resulted in an increase (P < 0.05) in serum P4, which declined following removal. In Experiment 1, serum P4 concentration was significantly lower from Day 9 to 14 (P < 0.05) and Day 14 CL weight was lower in the PRID® Delta Day 3 to 7 group than the placebo or control groups. P4 supplementation from Day 3 to 5 (17.0 ± 1.4 mm) or Day 3 to 7 (11.3 ± 2.3 mm) increased conceptus length compared to the placebo (2.1 ± 1.8 mm). In Experiment 2, serum P4 was significantly lower in the two supplemented groups following PRID® Delta removal compared with the placebo (P < 0.05) and was associated with a lower CL weight in the Day 3 to 7 group. Supplementation from Day 3 to 5 (94.0 ± 18.8 mm) or Day 3 to 7 (143.6 ± 20.6 mm) increased conceptus length on Day 16 compared to the placebo (50.3 ± 17.4 mm). Conceptus length was strongly correlated with the concentration of IFNT in the uterine flush (r = 0.58; P = 0.011) and spent culture medium (r = 0.68; P < 0.002). These findings highlight the somewhat paradoxical effects of P4 supplementation when given in the early metoestrus period in terms of its positive effect on conceptus development and its potentially negative effects on CL lifespan. Supported by CEVA Sante Animale and Science Foundation Ireland (07/SRC/B1156).

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