Uterine Cytokine Production During the Menstrual Cycle and Preimplantation Stages in Mice

Female reproduction is the only system subjected to well defined periodic changes. The final stage of the menstrual cycle in mammals is the maturation of the ovum and the preparation of the female organism to support fetal development fertilization. Once pregnancy occurs, both maternal and fetal sites emit regulatory signals to ensure embryo development and maternal protection against a graft versus host (GvH) reaction initiated by the semi-allogeneic fetus. We and others have previously shown that each day of fetal development in mice is characterized by different cytokine production, detected not only at the proximity of the feto-placental unit (decidua, uterus), but also in maternal lymphoid organs (spleen), as well as in the serum. In the present study, we concentrated on the menstrual cycle and the preimplantation stages of pregnancy and defined the levels of GM-CSF, IL-10, IL-6, and IL-3 in the murine uterus during anoestrus, proestrus, oestrus, and second and third day of gestation. We show by immunofluorescence and ELISA techniques that GM-CSF is maintained at high levels during anoestrus, proestus, oestrus, and the second day of pregnancy while dropping on the third day. IL-3 levels are found elevated during proestrus, second and third day of gestation, IL-6 increases essentially during proestrus, whereas the production of IL-10 was detected during oestrus and the early stages of pregnancy. Immunoperoxidase staining on frozen sections of uteri during the early gestational period localize GM-CSF and IL-3 production in the endometrium, IL-10 in the endometrium on the second day of pregnancy, and endometrium/myometrium on the third day. Low levels of IL-6 could be detected in the endometrium/epithelium on the second day and endometrium/myometrium on the third day of gestation. The role of IL-3, IL-10, and, to a lesser degree, IL-6 is fortified by the embryo itself, since these cytokines were found to be produced by blastocysts as well. These results demonstrate the existence of a specific distribution of lymphokines within the uterine tissue, the role of which is being discussed.