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At the human feto-maternal interface, trophoblasts differentiate towards extravillous trophoblasts (EVTs) and form the cell column. EVTs acquire invasive activity in the distal part of the cell column and begin to migrate into the maternal tissue. We previously reported that dipeptidyl peptidase IV(DPPIV) is expressed on EVTs in the proximal part of cell column and is involved in the inhibition of their migration. Because DPPIV has been shown to degrade several chemokines, we examined possible roles of chemokines in EVT migration.Immunohistochemistry demonstrated that C-C chemokine receptor 1 (CCR1) was hardly detected on cytotrophoblasts and syncytiotrophoblast but was expressed on EVTs in the cell column. In vitro, CCR1 protein was also present on the surface of EVTs that grew out from chorionic villous explants cultured under 20% O2. Chemokines that can bind to CCR1 (CCR1 ligands), such as regulated on activation, normal T cell expressed and secreted (RANTES) and macrophage inflammatory protein-1α (MIP-1α), were confirmed in the decidual tissues by RT-PCR and immunohistochemistry. These CCR1 ligands promoted the migration of the EVTs that were isolated from the explant cultures in vitro. These results indicate that CCR1 is expressed on trophoblasts as they differentiate to EVTs and that CCR1 ligands produced from the decidual tissue induce EVT migration.By contrast, CCR1 was scarcely expressed on EVTs that grew out from villous explants cultured in 1% O2, indicating that a relatively high oxygenic environment is needed to induce CCR1 expression. Moreover, CCR1 expression on the isolated EVTs was significantly reduced in the presence of decidua-conditioned medium. Such regulation of CCR1 by surrounding oxygenic and decidual environments supports a close correlation between EVT invasion and their expression of CCR1.This study demonstrates that trophoblasts acquire CCR1 as they differentiate to an invasive phenotype at the villus-anchoring sites and indicates a novel role for the chemokine-CCR1 system in the initial step of trophoblastic invasion towards the maternal tissue.

In early pregnancy, human extravillous trophoblasts (EVTs) invade and remodel maternal arteries. We have previously demonstrated that CCR1 is expressed on perivascular/endovascular trophoblasts and that CCR1 ligands promote EVT migration. In this study, we examined the physiologic roles of platelet-derived chemoattractants on EVT invasion. By immunohistochemistry, maternal platelets were localized among endovascular trophoblasts within the lumen of spiral arteries. Extracellular matrices (ECMs) were also detected among endovascular trophoblasts and platelets, suggesting that the platelets in these arteries were activated by ECMs. In vitro, platelets attached to EVTs isolated from human villous explant cultures and expressed P-selectin on the cell surface. Platelets significantly enhanced migration of EVTs without affecting proliferation of EVTs or secretion of MMP-2 or MMP-9. The invasion-enhancing effect of platelet-derived culture medium on EVTs was neutralized by anti-CCR1 antibody. Heat treatment completely abrogated the invasion-promoting effects of platelet-derived culture medium, but charcoal stripping did not. Platelets also induced endovascular trophoblast-like morphologic changes and integrin ␣1 expression in EVTs during 48-hour culture. These findings suggest that maternal platelets activated in the spiral arteries can regulate trophoblastic vascular infil IntroductionIn the human placenta, cytotrophoblasts show 2 distinct patterns of differentiation. In floating villi, cytotrophoblasts differentiate into syncytiotrophoblasts and form the syncytial layer while, at villousanchoring sites, cytotrophoblasts differentiate into extravillous trophoblasts (EVTs) and form the stratified structure called the cell column. After EVTs lose proliferative activity and acquire migratory activity in the cell column, 1 the cells begin to migrate into the decidual tissue (interstitial trophoblasts) or toward maternal blood vessels. Interestingly, EVT migration is directed preferentially to the uterine spiral arteries. 2 EVTs that migrate around the blood vessels (perivascular trophoblasts) destroy the muscular linings, and those that migrate along the vascular lumen (endovascular trophoblasts) replace the endothelium. Thus, the maternal arteries are remodeled into low-resistance tubes that are unable to constrict. This process ensures adequate placental perfusion and contributes to the successful establishment of pregnancy. 3 In fact, insufficient physiological remodeling has been reported in cases of preeclampsia and intrauterine fetal growth retardation. 4 In contrast to other organ constructions in the embryo and placenta, this extraembryonic tissue remodeling occurs in maternal tissues and requires both maternal and embryo-derived cells for cooperative tissue construction. From this perspective, this process is more complex than those involved in organ development during embryogenesis.Vascular infiltration of EVTs at the implantation site is mainly observed in humans and primates. 2 Therefore, analysis of the mech...

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To investigate immune-endocrine interactions between the embryo and the mother early in pregnancy, we examined the effects of human chorionic gonadotropin (HCG) on IL-8 production by peripheral blood mononuclear cells (PBMC). Recombinant HCG promoted IL-8 secretion by PBMC derived from nonpregnant women. The induction of IL-8 mRNA expression was observed after 30 min of HCG stimulation. Adsorption of the HCG with anti-HCG antibodies confirmed the specificity of this effect. The translocation of nuclear factor kappaB into the nucleus and subsequent IL-8 production were observed mainly in monocytes, and IL-8 production was reduced when a proteasome inhibitor was added to inactivate nuclear factor kappaB. Although fluorescein isothiocyanate-labeled HCG was bound to the majority of monocytes, cell surface expression of HCG receptor was hardly detected. IL-8 production by HCG was not affected by inhibitors of protein kinases A and C. In contrast, this stimulation was attenuated by D-mannose, which inhibits binding to C-type lectins. The basal IL-8 production by PBMC from women early in pregnancy was significantly elevated, compared with that from nonpregnant women. This study showed that human monocytes respond to HCG and secrete IL-8 through a pathway different from the HCG receptor system, suggesting that this glycoprotein hormone can react with not only endocrine cells but also immune cells early in pregnancy, probably via primitive systems such as C-type lectins.