| During pregnancy, the expression of several cytokines in the hypothalamus-pituitary gland-gonad axis were regulated through the complex neuro - endocrine - immune network, the changes or disorders of the expression of these cytokines caused by certain external factorsoften cause a variety of diseases and even pregnancy termination. Currently, the regulation and mechanism of the control and interaction of these cytokines during pregnancy were not confirmed. As reported that, Interleukin -18 (IL-18), insulin-like growth factor -1 (IGF-1) andγ-interferon (IFN-γ) are involved in the regulation of pregnancy, but the mutual regulation of these cytokines during pregnancy was less clear. In this research, immunohistochemical SP method was used to study the distribution of IGF-1 and IL-18 expression in the hypothalamus-pituitary gland-gonad axis during pregnancy, the influence between IFN-γ, IGF-1 and IL-18 expression, also image analysis system was use to analyzed its expression too. Fluorescent quantitative RT-PCR was used to detect the expression of IL-18 mRNA and IGF-1mRNA of the rat ovary and uterus after embryo implanted, and its expression after injection of IFN-γin the vaginal wall meanwhile, ELISA method was used to assay the expression of IL-18 and IGF-1 of the peripheral blood, and combined with microscopic and morphological analysis of the infection of IFN-γto pregnancy. All these offer the nerve biological research data for the mechanism of embryo loss during early pregnancy. The results of this research were as follows:1.During rat pregnancy, IGF-1 and IL-18 were expressed in a wide range of rat's 21 thalamencephalon nuclei, such as hypothalamus, periventricular nucleus, supraoptic nucleus, preoptic large nucleus, medial preoptic nucleus, preoptic nucleus, suprachiasmatic nucleus, the bow shaped nucleus, and so on; existed in the adenohypophysis and the neurohypophysis; and also expressed in the ovarian granulosa luteal cells, the growth of follicles, mature follicles, endometrial stromal cells, uterine epithelial cells, uterine smooth muscle cells, and vascular endothelium. This showed that IGF-1 and IL-18 play an important way on the function of pregnancy through the pathway of hypothalamus - pituitary - gonadal axis.2.The expression of IGF-1 and IL-18 in the pregnant rat hypothalamus - pituitary - gonadal axis are different during the stages of pregnancy. The expression of IGF-1 in thalamencephalon was increased during early implantation, implantation, plant continues, lower during the middle of pregnant, and espression higher in the third trimester of pregnancy than the middle. The expressed of IL-18 in thalamencephalon was descended during early implantation and implantation, and significantly increased post-implantation. This showed that IGF-1 and IL-18 have different characteristics spatially and temporally. IGF-1 expression in embryo implantation and late pregnancy showed that IGF-1 had important role in regulating embryonic development and delivery, while expression in the ovary and uterus, showed that IGF-1 could regulate the function of follicle and corpus luteum, thus affecting the generation of ovarian steroid, and involved in the regulation of immune of the maternal-fetal interface. Therefore IGF-1 and IL-18 synergy created the immune microenvironment for the maintenance of pregnancy.3. IGF-1 and IL-18 expression in rat thalamencephalon was different during the pregnancy phase, mainly in the hypothalamus preoptic periventricular nucleus, supraoptic nucleus, preoptic large nucleus, medial preoptic nucleus, preoptic nucleus, suprachiasmatic nucleus, arcuate nucleus and other major nuclei, which indicated that the hypothalamic preoptic area was concerned with the regulation of the pregnancy. 4. The expression of IGF-1 and IL-18 of the hypothalamus - pituitary - gonadal axis in pregnant rats acted different after injecting with different doses of IFN-γ. In detail, after the IFN-γinjection of 100IU/g, 500IU/g to rats, the expression of IGF-1 and IL-18 in hypothalamic preoptic nucleus and other nucleus all decreased. The different expressions of IGF-1 and IL-18 were also observed in other nuclei of the hypothalamus and pituitary, uterus and ovary. In peripheral blood, The expressions of IGF-1 and IL-18 in the hypothalamus - pituitary - gonadal axis were decreased in a different extent. These results suggested that the high dose of IFN-γshowed the downregulation effecton the expression of IGF-1 and IL-18 in the pregnant rat hypothalamus - pituitary - gonadal axis and that in the peripheral blood during early pregnancy. This demonstrated that the regulation of IFN-γon the pregnancy was a complex process.5. High dose injection of IFN-γ(500 IU/g) to the early pregnant rats could result fetal loss and pregnancy termination. The possible reason was the downregulation of the IGF-1 in the uterine and ovarian and IL-18 in blood. This result suggested that high doses of IFN-γwas one of keys that disorder the disorder of immune regulation system.6. Low dose of IFN-γto aborted rats could increase the expression of IL-18mRNA and IL-18 protein, in the uterus and ovary. Meanwhile, it also increased the IL-18 level, which was close to the normal group. The result suggested that low dose of IFN-γcould regulate the level of some cytokines, which was important to the maintenance of pregnancy.7. After mifepristone induced abortion, the levels of IGF-1 and IL-18 in the serum were all decreased, however, a little re-increase has been determined after the injection of IFN-γ. The possible reason was the regulation of IL-18 and IGF-1 levels of the pregnant rats hypothalamus - pituitary - reproductive axis for the inhibition to the inflammation caused by abortion, also for the the maintenance of pregnancy. This result suggested that the levels of IL-18 and IGF-1 in the peripheral blood of early pregnancy rats, was something valuable to fetal loss and abortion.8. There was a close expression relationship among IFN-γand IGF-1, IL-18. During the normal pregnancy, the decrease of IGF-1 and IL-18 expression broke down the balance of Th1/Th2 type cytokines and resulted the termination of pregnancy. However, the low dose of IFN-γcould influence the immune microenvirionment of maternal-fetal interface, regulate the balance of Th1/Th2 type cytokines, and maintain pregnancy. This suggested that IFN-γact an an important role in the prevention of abortion in early pregnancy.
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