Review
Interferons and the maternal–conceptus dialog in mammals

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Abstract

Two-way communication between the conceptus and the mother during early pregnancy is essential if the pregnancy is to survive. In this review, our primary focus is on biochemical communication between the conceptus and mother in the ruminant ungulate species. We emphasize, in particular, the role played by interferon-tau (IFNT) in triggering maternal responses in cattle and sheep and how maternal factors intervene to up-regulate IFNT gene (IFNT) expression in trophoblast. However, we also consider the possibility that different signaling cytokines or the physical presence of trophoblast may induce a partial IFN response in endometrium of those species where there is no evidence for large scale trophoblast IFN production. Conceivably, disparate signaling mechanisms trigger common downstream events necessary to secure a successful pregnancy.

Introduction

For the early mammalian conceptus to survive, it must intervene in maternal physiology to block ovarian cyclicity and ensure that the production of progesterone from the corpus luteum (CL) is maintained. The conceptus needs also to exploit space offered through the uterine endometrium, intensify its ability to access maternal metabolic resources, and survive scrutiny and potential destruction from a potentially hostile environment. The mother in her turn must avoid excessive exploitation by gaining some measure of control over the demands of the conceptus she nurtures. She must also be capable of assessing the fitness of her future progeny as early as possible during her pregnancy so that decisions can be made about whether the pregnancy should survive. It is not surprising therefore that two-way communication between the conceptus and the mother is established relatively early in embryo development, and that pregnancy loss is at its zenith before implantation is completed. Less than robust signaling from the conceptus and a failure of the mother to either respond to or reciprocate conceptus signals, which would lead to a lack of synchrony between the partners, likely contribute to this wastage [1].

In this review we report how interferons have assumed a role as the primary early signal from the conceptus to the mother in some species of artiodactyl, but also speculate that an “interferon” response by the mother may play a much wider role than previously suspected in establishment of pregnancy in mammals.

Section snippets

Initiation of conceptus signaling

The general aspects of conceptus development from fertilization up to the time that the blastocyst hatches from the zona pellucida are relatively similar across all eutherian mammals [2], [3]. Although there are differences in the timing of these events and where they occur in the reproductive tract of the mother, blastocyst formation is generally initiated when the conceptus enters the uterus. Hatching, which rapidly follows blastocyst formation, allows the conceptus to escape the enclosing

IFNT production by the ruminant conceptus

More than two weeks pass before the conceptuses of ruminants begin to attach to the uterine wall and initiate the process of placentation, although the pre-implantation trophoblast grows robustly in size and particularly in length during this time while remaining free within the uterine lumen, much like a parasitic worm in the intestine of a host. Possibly as an outcome of this delay in forming an intimate contact relationship with the maternal endometrium, ruminants have evolved a unique

Transcriptional control of IFN expression in trophoblast and the role of the mother

In comparison with other Type I IFN, IFNT expression is unique in at least four respects: it is confined to the ruminant ungulates; there is lack of viral inducibility; expression is restricted to embryonic trophectoderm; and high level synthesis is sustained over several days and then terminates. The IFNT are silent in the embryo, the placenta after it forms, and, as far as can be judged, in all tissue of the adult animal. By contrast, expression of related Type I IFN genes occurs in response

The action of IFNT on maternal endometrium

There is little evidence that IFNT released by the conceptus has a generalized effect on tissues outside the reproductive tract, although there are mounting indications of an IFN response occurring in the ovary as well as the endometrium of pregnant ewes and of ewes in which IFNT has been infused into the uterine lumen [36]. It is unclear whether this expression of IFN-stimulated genes (ISGs) either plays a role in luteal protection or whether it arises as the result IFNT reaching the ovary

IFN-gamma (IFNG) and IFN-delta (IFND) in the pig

The identification of IFNT in the sheep and the cow led to a search for IFN production by the conceptuses of other species. Our laboratory initially found evidence for antiviral factors associated with elongating d-12 pig [47] and pre-implantation mouse conceptuses [48], but was unable to identify a specific IFN. The nature of the antiviral factor released by mouse blastocysts still remains an enigma, but others successfully demonstrated that elongating pig trophoblast released two IFN

IFN in maternal conceptus dialog in the mouse and human

IFN production by pre-implantation conceptuses is not well documented in species other than the ruminant and pig, although, as described above, the mouse blastocyst may produce an antiviral response in cells in its immediate environment [48] and antiviral activity associated has been detected in late stage mouse placentas [57]. Importantly, however mice lacking a functional Type I IFN receptor are fertile and can carry a litter of pups to term [58], [59]. It therefore seems unlikely that

Evidence for a modified IFN response in endometrium of pregnant rodents and women

There is accumulating evidence that some genes responsive to IFN become up-regulated at implantation sites in the mouse [72], [73], [74], rat [75] and in the decidual tissues of pregnant women and baboons [76]. A similar increased expression of IFN-regulated genes has been observed after microarray analysis of human endometrial stromal cells that were either exposed to medium conditioned by extravillous cytotrophoblast [77] or co-cultured with first trimester trophoblast explants [78]. One

Summary

In summary, successful pregnancy in eutherian mammals requires both changes in ovarian physiology to prevent luteolysis and extensive alterations in the uterine environment to support embryo development. In ruminants, a recently evolved Type 1 IFN, the IFNT, serves as the focal point for maternal–conceptus dialog in early pregnancy. Its production by the ruminant conceptus has one well-established function unique to this sub-order, namely to modulate release of the uterine luteolysin, PGF and

Acknowledgement

The work from this laboratory was supported by NIH Grant HD21896.

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