The regulation of peripheral blood and uterine NK cell is very important for the achievement and maintenance of successful pregnancy. Natural cytotoxicity receptor (NCR) including NKp46 is unique receptor on NK cell that has functions for NK cell cytotoxicity and cytokines production. We have firstly shown the lower expression of NKp46 on NK cells in non-pregnant women with recurrent pregnancy loss (RPL) and implantation failure. Besides, that lower expression of NKp46 on NK cell was detected in pregnant women with a history of RPL, pregnancy women with pregnancy induced hypertension and women with pelvic endometriosis. So, the lower expression of NKp46 on NK cells may be a common phenomenon in reproductive failure and cause abnormal cytokines production by NK cells. In this review, the lower expression of NKp46 on NK cell for various situation of reproductive failure was shown and discussed.

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Protease system is an essential mechanism for human body which contains various molecule including its inhibitors. In human pregnancy, this system takes an important role on trophoblast invasion, spiral artery remodeling and the maintenance of the course of pregnancy. In this review, we describe roles of proteases (matrix metalloproteinases, plasminogen activators and inhibitors) in early pregnancy, especially on placentation. A radical switch of the placentation process from invasive trophoblast invasion (until 10w GA) to spiral artery remodeling (12 to 15w GA, which now regarded as a key pathophysiology of the complicated human pregnancy if it failed) is considered to be owe to the protease system alteration on invasive trophoblast and uterine natural killer cells. Further research into protease system in human reproduction is needed for understanding of mysterious establishment of early human pregnancy.

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Problem: BNC containing hepatitis B virus surface antigen consists of approximately 50-nm hollow particles displaying a human hepatocyte-recognizing molecule(pre-S1 peptide). BNC has been used as an HB vaccine for the last two decades. In this study, we optimized the BNC as a new drug delivery system(DDS)for uterus.Method of Study: The N terminal of Pre-S1 peptide was replaced with the TAT(trans-activating transcription factor)peptide. The Cy5.5 labeled BNC was transferred into the murine uterine cavity. The distribution of BNC was observed by in-vivo imaging system and also by immunohistochemistry. The luciferase expression plasmid DNA was incorporated into BNC using liposome(Coatsome EL-01-D). The luciferase expression plasmid DNA was transferred into uterine cavity using TAT-BNC-liposome complex. The efficiency of gene transfection was analysed by luciferase assay.Results: TAT-BNCs temporary stayed in uterus. BNCs were observed in luminal and glandular epithelial cells, but not in stroma and myometrium. The transfection efficiency of the TAT-BNC–liposome complex was significantly higher than lipofection.Conclusion: These results suggest that BNC could be an applicable DDS for uterus. In this study, we replaced the N terminal of Pre-S1 peptide with TAT peptide. However, it is replaceable with sugar chains and antibodies. Recently there are some reports that some of special sugar chains are expressed on uterine endometrium during pregnancy and uterine cancer. If we can find specific sugar chains or cell surface antibodies on uterine endometrium for reproductive dysfunction and uterine cancer, this DDS system can be more targetable.

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Objectives:Lysophosphatidic acid(LPA)is a new class lipid mediator and exerts varied physiological and pathological functions through the binding to cell- membrane specific receptors. A secreting protein, autotaxin(ATX)is a key enzyme to determine local LPA production.We reported that placental ATX mRNA amount of the women with pregnancy induced hypertension(PIH) were significantly lower than that of normal women. Impaired implantation was reported in mice deficient in LPAR3, one of LPA receptors, suggesting the critical role of this pathway in reproduction. We aimed to explore the regulatory role of trophoblast cell function by ATX-LPA-LPAR3 pathway and its association with the pathology of PIH.Methods:We analyzed the local expression of ATX and LPAR3 in human placenta using immunohistochemistry. Next, we transfected LPAR3 gene to HTR-8/SVneo, a trophoblastic cell line, and stimulated it with the specific agonist of LPAR3. Real-time PCR was conducted to examined the impact of the stimulation on the expression level of angiogenic factors in LPAR3-transfected cells.All placental samples and the experiments were conducted under the approval of the ethical committee in our facility.Results:ATX-specific staining is confirmed in all types of trophoblasts. The expression of LPAR3 was restricted to differentiated trophoblasts including syncytiotrophoblast and extra-villous trophoblasts.LPAR3-transfected HTR-8/SVneo enhanced cyclooxygenase-2(COX-2), interleukin-8(IL-8), and vascular endotherial growth factor(VEGF)expression remarkably upon the stimulation with a specific agonist to LPAR3.Conclusion:Our findings revealed that ATX-LPA-LPAR3 pathway regulates the expression of angiogenic factors in trophoblasts. Reduced ATX production occuring in preeclamptic placentas might diminished the angiogenic property in trophoblasts, consequently leading to aberrant placentation.

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