A role for cytokines in early pregnancy.

Cytokines are expressed in a variety of cell types of the reproductive system, although in most instances their functions are not understood. There are, however, a few instances where a role in early pregnancy has been established. First, preimplantation conceptuses of ruminant ungulate species, such as cattle, sheep and goat, secrete a unique Type I interferon (IFN-tau). By mechanisms that are still unclear, IFN-tau prevents the destruction of the corpus luteum and hence ensures the continued production of progesterone which is essential for continuation of pregnancy. Most like the IFN-tau prevent lutcolysis by modulating the output of a luteolytic hormone, prostaglandin F2 alpha, from the uterus. Depsite this involvement in pregnancy, the IFN-tau possess similar antiproliferative and antiviral activities to other Type I IFN, 1 lambda e.g. IFN-alpha. There are 4-5 genes for IFN-tau in sheep and cattle whose promotor regions are highly conserved and distinct from those of other Type I IFN. These genens are not virally inducible and are expressed only in the trophectoderm (outer epithelium of the developing placenta) from the time of blastocyst hatching to implantation. Leukemia inhibitory factor (LIF) is a multi-functional cytokine which is expressed by uterine endometrium of pregnant mice around day 4 of pregnancy. Female mice lacking a functional LIF gene are fertile but their blastocysts fail to implant, strongly implicating the cytokine in maternal control of implantation. Colony stimulating factors (CSF) are a family of proteins (GM-CSF, CSF-1, G-CSF, and IL-3) that stimulate the cellular proliferation and induction of terminal differentiation of hemopoietic progenitor cells. CSF-1 is expressed in the uterine endometrium of the mouse and human during early pregnancy and its receptor, fms, is present on trophoblast. The osteopetrotic mouse, which represents a natural "knockout" of the CSF-1 gene, exhibits a low rate of fetal implantation and poor fetal viability. It seems likely that CSF-1 expression by the uterus influences growth and differentiation of the placenta. Although different species may utilize different strategies for ensuring developmental and endocrinological coordination between the embryo and the mother, these three examples illustrate that cytokines are likely to be major participants as autocrine factors that direct the events of early pregnancy and not simply as modulators of the maternal immune system.