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PubMed2000

Cytotoxic effects of tumour necrosis factor (TNF)-alpha and interferon-gamma on cultured human trophoblast are modulated by fibronectin.

Tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, produced by maternal inflammatory cells, may compromise trophoblast survival at the trophoblast-maternal interface and notably in the placental bed which is invaded by trophoblast. Extracellular matrix components, e.g. fibronectin, may enhance trophoblast survival. A possible protective effect of fibronectin against toxic effects of TNF-alpha and IFN-gamma was investigated in cultured trophoblasts isolated from six human term placentas, grown on uncoated and fibronectin-coated plastics. IFN-gamma and increasing doses of TNF-alpha resulted in decreasing viability of trophoblast on uncoated as well as fibronectin-coated dishes, as shown by 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assays, but for each TNF/IFN treatment condition viability on fibronectin was higher (P < 0.001). Epidermal growth factor (EGF), a growth factor reported to protect against TNF-alpha/IFN-gamma induced toxicity, resulted in further increased viability, but not if IFN-gamma was included in the treatment. EGF caused increased fibronectin secretion into the medium (P < 0.001), and double cytokeratin/fibronectin immunostaining confirmed the trophoblastic nature of fibronectin secreting cells. We conclude that fibronectin increases viability, but does not completely abolish the cytotoxic action of TNF-alpha and IFN-gamma on trophoblast. The protective effect of EGF may be related to stimulation of fibronectin secretion by trophoblast.

Cell Survival↗
PubMed2003

Regulation of FasL/Fas in human trophoblasts: possible implications for chorioamnionitis.

Chorioamnionitis is a common cause of premature birth and is associated with significant morbidity and mortality in the mother and infant. Preterm birth shares similarities with rejection of the fetal allograft, which is characterized by increased apoptosis of placental trophoblasts. We hypothesized that there is increased trophoblast apoptosis in chorioamnionitis and that this increased apoptosis is mediated by the Fas ligand (FasL)/Fas pathway. To test our hypothesis, we examined placental villous tissues from patients with chorioamnionitis and used the TUNEL assay to demonstrate enhanced trophoblast apoptosis in patients with chorioamnionitis. When the same samples were stained for Fas, there was increased trophoblast Fas expression in patients with chorioamnionitis. To define the mechanisms responsible for this increase in trophoblast apoptosis, we cultured villous explants from uncomplicated term placentas with proinflammatory cytokines and demonstrated a marked increase in trophoblast apoptosis. By blocking FasL, we reduced tumor necrosis factor alpha-induced and interferon gamma-induced apoptosis. These data suggest that chorioamnionitis is associated with increased trophoblast apoptosis and enhanced trophoblast Fas expression. As a complement to our in vivo study, we demonstrated that cytokine-induced trophoblast apoptosis is mediated in part by the FasL/Fas pathway, suggesting that cytokines promote sensitivity to Fas-mediated apoptosis. These mechanisms may be important in perpetuating inflammation in the placental microenvironment and may contribute to the pathogenesis of chorioamnionitis.

Adult↗
PubMed2005

Difference in progesterone-receptor isoforms ratio between early and late first-trimester human trophoblast is associated with differential cell invasion and matrix metalloproteinase 2 expression.

The expression profile of the progesterone-receptor isoforms and progesterone regulation of matrix metalloproteinase 2 (MMP2) were investigated in early and late first-trimester trophoblast cells. Human trophoblast cells were obtained from legal abortions (6-12 wk of gestation). Purity of 95-98% was verified using immunohistochemistry with specific antibodies. Evaluation of cell count was performed with XTT Reagent kit, and invasion was tested using Matrigel invasion assay. Zymography was used to detect proteolytic activity, and Western blot immunoassay was used to study protein concentration. Gene expression of PGRB, PGR, and MMP2 was studied using reverse transcription-polymerase chain reaction with the housekeeping gene GAPDH used for normalization. Promoter activity was determined using luciferase reporter assay. Differential progesterone-receptor profile was documented with the dominance of PGRB in early trophoblast and the dominance of PGRA in late trophoblast. This differential profile is compatible with the inverse effect of progesterone on the two cell populations, decreasing invasion and gelatinase expression in the early first-trimester trophoblast and increasing invasion and gelatinase expression in the late first-trimester trophoblast. A decrease in MMP2 promoter activity in early trophoblast cells exposed to progesterone suggests that MMP2 expression is regulated by progesterone at the transcriptional level as well. Early trophoblast cells transfected with expressing vector for PGR encoding PGRA revealed less MMP2 activity and reversal of its response to progesterone similar to the effect observed in late trophoblast cells.

Embryo Implantation↗
PubMed2006

Coordinated regulation of human trophoblast invasiveness by macrophages and interleukin 10.

Trophoblast invasion and modification of the spiral arterioles are essential for the establishment of adequate uteroplacental blood flow during pregnancy. However, such vascular remodeling is deficient in preeclampsia. This disease is also associated with increased maternal levels of circulating proinflammatory cytokines such as tumor necrosis factor (TNF) and reduced levels of immunoregulatory cytokines such as interleukin 10 (IL10). We have previously shown that activated macrophages inhibit trophoblast invasiveness in vitro. The present study demonstrates that IL10 interferes with the invasion-inhibitory effect that activated macrophages exert on trophoblast cells. Co-culture experiments revealed that human lipopolysaccharide (LPS)-activated macrophages inhibited the ability of immortalized HTR-8/SVneo human trophoblast cells to invade through reconstituted extracellular matrix. This effect of activated macrophages on trophoblast invasiveness was paralleled by decreased expression of urokinase plasminogen activator receptor (PLAUR) on the surface of trophoblast cells, and by increased secretion of plasminogen activator inhibitor type 1 (SERPINE1). Exposure of LPS-treated macrophages to IL10 prior to co-culture prevented their ability to inhibit trophoblast invasion, PLAUR expression, and to stimulate SERPINE1 secretion. Interleukin 10 prevented macrophage activation by LPS as determined by the lack of secretion of TNF in the culture medium, and a neutralizing TNF antibody completely blocked the effect of macrophages on trophoblast invasion. These results indicate that decreased circulating levels of IL10 associated with preeclampsia may contribute to inadequate trophoblast invasion and remodeling of the uterine spiral arterioles.

Cell Movement↗
PubMed2004

c-mos immunoreactivity aids in the diagnosis of gestational trophoblastic lesions.

C-mos is an important proto-oncogene involved in the mitogen-activating protein kinase pathway. This study was designed to explore c-mos immunoreactivity in gestational trophoblastic lesions and compare it with immunoreactivity in normal placentas as well as other gynecological lesions and germ cell tumors using antibody P-19. The immunohistochemical distribution of c-mos in 159 cases of gynecological lesions and 26 germ cell tumors using formalin-fixed, paraffin-embedded tissues was evaluated. The lesions included 45 (32 complete and 13 partial) hydatidiform moles, 17 choriocarcinomas, 5 placental site trophoblastic tumors, 18 squamous cell carcinomas and 5 adenocarcinomas of the cervix, 11 endometrial carcinomas, 9 ovarian carcinomas, 4 primary peritoneal papillary serous carcinomas, 9 low-grade endometrial stromal sarcomas, 4 epithelioid leiomyomas, 6 leiomyosarcomas, and 26 gem cell tumors (3 embryonal carcinomas, 5 yolk sac tumors, 6 immature teratomas, and 3 mature teratomas from the ovary; 9 testicular seminomas). Twenty-six normal placentas also were included for comparison. Among cases of gestational trophoblastic diseases, c-mos immunoreactivity was found in all hydatidiform moles and choriocarcinomas, but in none of the placental site trophoblastic tumors. The c-mos staining pattern was similar in trophoblastic diseases and normal placentas with strong expression in syncytiotrophoblast, moderate expression in villous intermediate trophoblast, and predominantly negative expression in implantation site intermediate trophoblast, chorionic-type intermediate trophoblast, and villous cytotrophoblast. All the nontrophoblastic tumors, including carcinomas, sarcomas, and germ cell tumors, were negative for c-mos expression. Immunohistochemical detection of c-mos is useful in differentiating choriocarcinoma from placental site trophoblastic tumor and nontrophoblastic tumors of the female genital tract that may sometimes cause problems in differential diagnosis.

Biomarkers, Tumor↗
PubMed1983

Immunological studies of human trophoblast: markers, subsets and functions.

People have many different reasons for wanting to know how the allogeneic relationship in normal human pregnancy is successful, but this question is far from being answered. Meanwhile, investigators will continue to use the ideas, approaches and tools with which they have experience and in which they have placed their confidence. Some study the factors which regulate immune functions in the fetus (for review see Murgita & Wigzel 1981); other focus more on the mother (for review see Rocklin et al. 1979); while yet others examine specialized aspects of abnormal pregnancies such as spontaneous abortion (Gill 1983). Although no one knows how the system operates to favor pregnancy, our particular bias is that trophoblast is the driving force which makes it work; for, without trophoblast, there is no pregnancy. This prejudice grew from our early observations of immunopathology in normal placentae (McCormick et al. 1971, Faulk et al. 1974, Faulk et al. 1980b, and reviewed by Faulk & Fox 1982) and was extended and amplified by experiments which showed that trophoblast, as well as antibodies to trophoblast, were able to impede allogeneic recognition as measured by specific inhibition of the mixed lymphocyte culture reaction (McIntyre & Faulk 1979 & 1979a). For a variety of reasons, many laboratories became interested in trophoblast-antigen biochemistry, and a burst of publications appeared on this subject (Faulk et al. 1977, Whyte & Loke 1979, Ogbimi et al. 1979, see review by Johnson et al. 1980). Some of this work confirmed and extended an earlier hypothesis from our laboratory that trophoblast membranes could serve as a hapten-carrier system where one group of trophoblast antigens (TA1) was the carrier, and a second group (TA2) was the hapten (Faulk et al. 1978). This hypothesis invoked a concept of trophoblast-lymphocyte cross-reactive antigens, an idea which was subsequently confirmed biochemically by showing human placental cell-surface antigens on peripheral blood lymphocytes (Hamilton et al. 1980). McIntyre and Faulk (1982, 1982a) later showed that these antigens were allotypic, and data have been provided in the above paragraphs to show that these components of trophoblast membranes are capable of serving as immunogens to stimulate the mother to mount immune recognition of her blastocyst. Indeed, it is presently our interpretation that successful nidation depends upon maternal recognition of the blastocyst, and that a lack of recognition results in spontaneous abortion, sometimes occurring so early that the mother is not aware that she was pregnant (Miller et al. 1980).(ABSTRACT TRUNCATED AT 400 WORDS)

Abortion, Habitual↗
PubMed1985

The sensitivity of placental trophoblast cells to intraplacental and allogeneic cytotoxic lymphocytes.

The NK-susceptibility of trophoblast cells to allogeneic and autologous intraplacental natural killer (NK), antibody-dependent (K), and mitogen-induced cell-mediated cytotoxicity was studied, using untreated and neuraminidase-treated trophoblast cells from normal, full-term deliveries. The work was preceded by systematic studies of placental cell separation and labelling techniques, and the effects of these techniques on the NK target, K562. The results indicated that maternal NK cells are present among intraplacental lymphocytes, but that their activity is lower than that of peripheral blood lymphocytes and they are not stimulated by interferon to the same extent as peripheral blood lymphocytes (PBL). Trophoblast cells were rarely susceptible to allogeneic NK cells, with low cytotoxicity at high effector-target cell ratios in only two of five experiments. Interferon (IF)-boosted NK cells mediated some cytolysis of trophoblasts in three of four experiments, but high effector/target cell ratios were also required for the effect to be observed. The trophoblast cells could be lysed, however, by K cells and lectin-induced cytotoxicity. Removal of surface sialic acid by neuraminidase treatment of the trophoblast cells had little effect on the susceptibility of these cells to unstimulated NK cells (one of four experiments), but resulted in susceptibility to IF-boosted NK cells in four of four experiments. Normal trophoblast cells did not compete in IF-NK(K562) assays and neuraminidase-treated cells competed weakly in only one of three such experiments, indicating that the NK "target structure" is only weakly expressed on human trophoblast cells. Intraplacental lymphocytes lysed autologous trophoblast cells to a lower extent than allogeneic PBL.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody-Dependent Cell Cytotoxicity↗
PubMed1996

Human trophoblast cell adhesion to extracellular matrix protein, entactin.

PROBLEM: Trophoblast interaction with endometrial extracellular matrix (ECM) is crucial during human embryo implantation and placentation. Entactin, a ubiquitous basement membrane glycoprotein, plays a central role in ECM assembly, cell attachment, and chemotaxis. The present study was conducted to examine the possible role of entactin in promoting human trophoblast adhesion. METHODS: Using an extended life span first trimester trophoblast cell line HTR-8/SVneo (HTR) and a cell adhesion assay, we measured the adherence of human first trimester trophoblasts to recombinant entactin and its domains. Also, we used flow cytometry and indirect immunofluorescence to detect the presence of integrins that may be involved in human trophoblast-entactin interaction; these methods were used to analyze HTR cells, as well as tissue sections and freshly isolated human trophoblasts from first trimester and term placenta. RESULTS: We found that first trimester trophoblast cells were highly adherent to entactin and its E and G2 domains but not to G1 or G3 domains. Using indirect immunofluorescence and flow cytometry, we found that both beta 1 and beta 3 integrin subunits were expressed on the surface of HTR trophoblast cells adhering to entactin; in contrast, beta 2 and beta 4 integrin subunits were not detected. In addition, we found that alpha v beta 3 was expressed on freshly isolated villous cytotrophoblasts and cytotrophoblast and syncytiotrophoblasts in tissue sections from term placenta. The beta 3 integrin subunit was expressed in cytotrophoblasts and syncytiotrophoblasts in villi of first trimester placental tissue sections. CONCLUSION: Recombinant entactin promotes human trophoblast cell adhesion through both its E and G2 domains and these specific adhesive interactions may be mediated by beta 1 and/or beta 3 class integrins.

Antigens, CD↗
PubMed1996

Effects of tumor necrosis factor-alpha on human trophoblast cell adhesion and motility.

PROBLEM: Adhesive interaction between trophoblast cells and uterine endometrial basement membrane is one of the critical processes in embryo implantation. This interaction is directly or indirectly regulated by hormones, growth factors, and cytokines. Since tumor necrosis factor-alpha (TNF-alpha) is synthesized by both decidual and trophoblast cells, we hypothesized that TNF-alpha may play a regulatory role in trophoblast cell invasion. To test this hypothesis, we have used in vitro models to determine the effect of TNF-alpha on human trophoblast cell adhesion and motility, two major steps in trophoblast invasion. METHODS: The effect of TNF-alpha on the motility of extended-lifespan first trimester trophoblasts (HTR) and JEG-3 choriocarcinoma cells was tested using the phagokinetic track motility assay. An in vitro adhesion assay was used to determine the effect of TNF-alpha on the adhesion of HTR and JEG-3 cells to laminin, a major basement membrane component. In addition, the effect of TNF-alpha on the surface expression of the laminin receptor beta 1 integrin subunit was examined using flow cytometry. RESULTS: HTR or JEG-3 cells strongly adherent to laminin which was not significantly altered by TNF-alpha treatment. We also measured the effect of TNF-alpha on the surface expression of beta 1 integrin on HTR and JEG-3 cells; no difference was observed between control and treatment groups. Interestingly, the motility of both HTR and choriocarcinoma JEG-3 cells was significantly inhibited by TNF-alpha. CONCLUSIONS: The role of TNF-alpha in human embryo implantation is currently unknown. Our data demonstrate that TNF-alpha does alter trophoblast cell adhesion to laminin, but significantly inhibits trophoblast cell motility in vitro, suggesting that TNF-alpha may play a regulatory role in trophoblast cell invasion.

Cell Adhesion↗
PubMed2001

Production of interferons and beta-chemokines by placental trophoblasts of HIV-1-infected women.

OBJECTIVE: The mechanism whereby the placental cells of a human immunodeficiency virus (HIV)-1-infected mother protect the fetus from HIV-1 infection is unclear. Interferons (IFNs) inhibit the replication of viruses by acting at various stages of the life cycle and may play a role in protecting against vertical transmission of HIV-1. In addition the beta-chemokines RANTES (regulated on activation T cell expressed and secreted), macrophage inflammatory protein-1-alpha (MIP-1alpha), and MIP-1beta can block HIV-1 entry into cells by preventing the binding of the macrophage-trophic HIV-1 strains to the coreceptor CCR5. In this study the production of IFNs and beta-chemokines by placental trophoblasts of HIV-1-infected women who were HIV-1 non-transmitters was examined. METHODS: Placental trophoblastic cells were isolated from 29 HIV-1-infected and 10 control subjects. Supernatants of trophoblast cultures were tested for the production of IFNs and beta-chemokines by enzyme linked immunosorbent assay (ELISA). Additionally, HIV-1-gag and IFN-beta transcripts were determined by a semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) assay. RESULTS: All placental trophoblasts of HIV-1-infected women contained HIV-1-gag transcripts. There were no statistical differences in the median constitutive levels of IFN-alpha and IFN-gamma produced by trophoblasts of HIV-1 infected and control subjects. In contrast, trophoblasts of HIV-1-infected women constitutively produced significantly higher levels of IFN-beta protein than trophoblasts of control subjects. Furthermore, the median levels of beta-chemokines produced by trophoblasts of HIV-infected and control women were similar. CONCLUSIONS: Since there was no correlation between the placental HIV load and the production of interferons or beta-chemokines, the role of trophoblast-derived IFNs and beta-chemokines in protecting the fetus from infection with HIV-1 is not clear.

CD4 Lymphocyte Count↗
PubMed2002

Identification of the white blood cell populations responsible for Th1 immunity to trophoblast and the timing of the response in women with recurrent pregnancy loss.

AIM: The purpose of this study was to identify the white blood cell populations responsible for Th1 immunity to trophoblast as evidenced in our in vitro assays following trophoblast activation and the timing of this response. STUDY DESIGN: Peripheral blood mononuclear cells (PBMC) were isolated from 32 nonpregnant women with a history of at least three prior first trimester spontaneous abortions of unknown etiology except their PBMC secreted Th1 embryotoxic cytokines in response to trophoblast stimulation. White blood cell populations were separated from PBMC by magnetic immunobeads and cultured with and without a trophoblast antigen extract. Supernatants from these cultures were added to two cell mouse embryos and after four days of culture assessment of blastocyst development was made to determine the white blood cell population responsible for embryotoxicity. In separate experiments trophoblast-activated PBMC culture supernatants were prepared over seven time points and individual Th1 cytokines (IL-2, INF-gamma, TNF-alpha) were measured by ELISA to determine the timing of the response to trophoblast stimulation. RESULTS: The white blood cell (CD45) populations responsible for embryotoxicity in response to trophoblast were T cells (CD3) and NK (CD56) cells. Levels of IL-2 peaked in the first 24 h of culture followed by TNF-alpha and IFN-gamma levels which peaked at 96 h of culture. CONCLUSIONS: Our data demonstrated that the white blood cell populations responsible for embryotoxicity in our in vitro assays, were both T and NK cells. The kinetics of the cytokine response to trophoblast found in our study parallels the time course of a typical Th1 cytokine response. The profile of secreted cytokines support our hypothesis that trophoblast can produce Th1 immunity in some women with recurrent pregnancy loss that have embryotoxic effects in vitro.

Abortion, Habitual↗
PubMed2002

Experimental modulation of cell-cell adhesion, invasiveness and differentiation in trophoblast cells.

The establishment of pregnancy in the human decisively depends on the competence of the early trophoblast to interact during implantation with (1). the uterine epithelium and subsequently (2). with the endometrial stroma and blood vessels. In the interaction with uterine epithelium cell-to-cell adhesion appears to be a critical element, involving initially (and astonishingly) apical cell poles of both epithelia. The subsequent invasion of the stroma includes both adhesive interactions with and degradation of extracellular matrix. How these different processes are regulated in detail remains largely unknown. While the invasiveness of the trophoblast is known to be regulated in local and temporal terms it has remained unclear so far whether trophoblast adhesiveness to cells and/or matrix is subject to a coupled regulation or whether both properties involve different, maybe sequentially effective, control mechanisms. It is also not known how the regulation of these activities is related to the differentiation pathways leading to the formation of noninvasive villous trophoblast serving endocrine as well as nutritive functions. This communication reviews experiments using normal cytotrophoblast cells isolated from first trimester or term placentae as well as malignant trophoblast (choriocarcinoma) cells treated with a panel of compounds known to modulate cell differentiation [retinoic acid, methotrexate, dibutyryl-cAMP, phorbol-(12-myristoyl-13-acetyl)-diester]. Parameters indicative of trophoblast differentiation [in particular chorionic gonadotrophin (hCG) secretion] as well as adhesion to uterine epithelial cells and invasion into extracellular matrix in vitro were monitored. While expression of differentiation parameters was increased by all drug treatments, adhesion to uterine epithelial cells in vitro was reduced. Modulation of invasiveness, however, followed a different pattern: while it was reduced in normal trophoblast cells it was even increased in choriocarcinoma cells with various substances. The response of cells with respect to production of extracellular matrix proteins or matrix-degrading proteinases showed a complex pattern that again lacked a stringent correlation with hCG production and adhesion, and in addition also with invasive behavior. These results suggest that adhesiveness of trophoblast to uterine epithelial cells and invasiveness into the uterine stroma (extracellular matrix) are subject to different control mechanisms. They support the view that trophoblast-endometrium interactions involve a cascade of various adhesion and migration processes whose cellular and molecular basis is complex but accessible to experimental investigation using a variety of available in vitro systems.

Antimetabolites, Antineoplastic↗
PubMed2003

Quantitative investigation of reproduction of gonosomal condensed chromatin during trophoblast cell polyploidization and endoreduplication in the East-European field vole Microtus rossiaemeridionalis.

Simultaneous determinations of DNA content in cell nuclei and condensed chromatin bodies formed by heterochromatized regions of sex chromosomes (gonosomal chromatin bodies, GCB) have been performed in two trophoblast cell populations of the East-European field vole Microtus rossiaemeridionalis: in the proliferative population of trophoblast cells of the junctional zone of placenta and in the secondary giant trophoblast cells. One or two GCBs have been observed in trophoblast cell nuclei of all embryos studied (perhaps both male and female). In the proliferative trophoblast cell population characterized by low ploidy levels (2-16c) and in the highly polyploid population of secondary giant trophoblast cells (32-256c) the total DNA content in GCB increased proportionally to the ploidy level. In individual GCBs the DNA content also rose proportionally to the ploidy level in nuclei both with one and with two GCBs in both trophoblast cell populations. Some increase in percentage of nuclei with 2-3 GCBs was shown in nuclei of the placenta junctional zone; this may be accounted for by genome multiplication via uncompleted mitoses. In nuclei of the secondary giant trophoblast cells (16-256c) the number of GCBs did not exceed 2, and the fraction of nuclei with two GCBs did not increase, which suggests the polytene nature of sex chromosomes in these cells. In all classes of ploidy the DNA content in trophoblast cell nuclei with the single GCB was lower than in nuclei with two and more GCBs. This can indicate that the single GCB in many cases does not derive from fusion of two GCBs. The measurements in individual GCBs suggest that different heterochromatized regions of the X- and Y-chromosome may contribute in GCB formation.

Animals↗
PubMed2004

Regulation of major histocompatibility complex class II gene expression in trophoblast cells.

Trophoblast cells are unique because they are one of the few mammalian cell types that do not express major histocompatibility complex (MHC) class II antigens, either constitutively or after exposure to IFN-gamma. The absence of MHC class II antigen expression on trophoblast cells has been postulated to be one of the essential mechanisms by which the semi-allogeneic fetus evades immune rejection reactions by the maternal immune system. Consistent with this hypothesis, trophoblast cells from the placentas of women suffering from chronic inflammation of unknown etiology and spontaneous recurrent miscarriages have been reported to aberrantly express MHC class II antigens. The lack of MHC class II antigen expression on trophoblast cells is due to silencing of expression of the class II transactivator (CIITA), a transacting factor that is essential for constitutive and IFN-gamma-inducible MHC class II gene transcription. Transfection of trophoblast cells with CIITA expression vectors activates both MHC class II and class Ia antigen expression, which confers on trophoblast cells both the ability to activate helper T cells, and sensitivity to lysis by cytotoxic T lymphocytes. Collectively, these studies strongly suggest that stringent silencing of CIITA (and therefore MHC class II) gene expression in trophoblast cells is critical for the prevention of immune rejection responses against the fetus by the maternal immune system. The focus of this review is to summarize studies examining the novel mechanisms by which CIITA is silenced in trophoblast cells. The elucidation of the silencing of CIITA in trophoblast cells may shed light on how the semi-allogeneic fetus evades immune rejection by the maternal immune system during pregnancy.

Animals↗
PubMed2005

Interferon-gamma alters the phagocytic activity of the mouse trophoblast.

Interferon-gamma (IFN-gamma) mediates diverse functions in bone marrow-derived phagocytes, including phagocytosis and microbe destruction. This cytokine has also been detected at implantation sites under both physiological and pathological conditions in many different species. At these particular sites, the outermost embryonic cell layer in close contact with the maternal tissues, the trophoblast exhibits intense phagocytic activity. To determine whether IFN-gamma affects phagocytosis of mouse-trophoblast cells, ectoplacental cone-derived trophoblast was cultured and evaluated for erythrophagocytosis. Phagocytic activity was monitored ultrastructurally and expressed as percentage of phagocytic trophoblast in total trophoblast cells. Conditioned medium from concanavalin-A-stimulated spleen cells significantly enhanced trophoblast phagocytosis. This effect was blocked by pre-incubation with an anti-IFN-gamma neutralizing antibody. Introduction of mouse recombinant IFN-gamma (mrIFN-gamma) to cultures did not increase cell death, but augmented the percentage of phagocytic cells in a dose-dependent manner. Ectoplacental cones from mice deficient for IFN-gamma receptor alpha-chain showed a significant decrease of the phagocytosis, even under mrIFN-gamma stimulation, suggesting that IFN-gamma-induced phagocytosis are receptor-mediated. Reverse transcriptase-PCR analyses confirmed the presence of mRNA for IFN-gamma receptor alpha and beta-chains in trophoblast cells and detected a significant increase in the mRNA levels of IFN-gamma receptor beta-chain, mainly, when cultured cells were exposed to IFN-gamma. Immunohistochemistry and Western blot analyses also revealed protein expression of the IFN-gamma receptor alpha-chain. These results suggest that IFN-gamma may participate in the phagocytic activation of the mouse trophoblast, albeit the exact mechanism was not hereby elucidated. Protective and/or nutritional fetal benefit may result from this physiological response. In addition, our data also shed some light on the understanding of trophoblast tolerance to inflammatory/immune cytokines during normal gestation.

Animals↗
PubMed1989

High density lipoprotein3 binding and biological action: high affinity binding is not necessary for stimulation of placental lactogen release from trophoblast cells.

High density lipoprotein (HDL3) binds with high affinity to many types of cells, but controversy exists concerning the nature and biological significance of the binding. We have recently demonstrated that HDL and apoproteins (apo)-AI, -AII, and -CI stimulate a specific and dose-dependent increase in placental lactogen (hPL) release from human trophoblast cells. To examine the possible relationship between HDL3 binding and stimulation of hPL release, we have characterized the binding of [125I]HDL3 to an enriched fraction of hPL-producing trophoblast cells. Binding studies were performed on trophoblast cells isolated by isopycnic centrifugation of collagenase/hyaluronidase-dispersed placental tissue and apo-E free-HDL3 (density, 1.125-1.215 g/ml). Scatchard analysis of binding studies performed at 37 C for 2 h revealed two classes of binding sites: 1) high affinity binding sites with a Kd of 9.7 +/- 2.2 micrograms/ml (1.3 x 10(-7) M) and 9.8 +/- 3.2 x 10(5) binding sites/trophoblast cell, and 2) low affinity binding sites with a Kd of 172.8 +/- 64.8 micrograms/ml (2.3 x 10(-6) M) and an estimated 3.2 x 10(6) sites/cell. As has been found in hepatocytes and other cells, the number of HDL3-binding sites per trophoblast cell (but not the binding affinity) decreased at lower incubation temperatures. In addition, HDL3 binding to trophoblasts cells did not require calcium and was not affected by prior treatment of the cells with pronase or trypsin. HDL3-binding sites on trophoblast cells, however, were not specific for HDL3. Low density lipoprotein (density, 1.063-1.055 g/ml), which does not stimulate hPL release, was nearly as potent on a molar basis as HDL3 in binding to the high and low affinity binding sites on trophoblast cells. Furthermore, nitrated HDL3, which does not compete for high affinity binding to trophoblast cells, stimulated hPL release. Although the characteristics of HDL3 binding to trophoblast cells are similar to those of other cells, these results strongly suggest that the binding of HDL3 to high affinity binding sites is not essential for HDL-mediated hPL release.

Binding Sites↗
PubMed1997

Endoglin regulates trophoblast differentiation along the invasive pathway in human placental villous explants.

Successful invasion of the maternal vascular system by trophoblast cells is a prerequisite for the establishment of a normal hemochorial placenta. Transforming growth factor-beta (TGFbeta) has been implicated in the regulation of trophoblast invasiveness into the uterus. Endoglin is a component of the TGFbeta receptor complex that binds beta1 and beta3 isoforms and is expressed at high levels on syncytiotrophoblast throughout pregnancy and is also transiently up-regulated on extravillous trophoblasts differentiating along the invasive pathway. We investigated the role of endoglin in a serum-free human villous explant culture system that allows the study of trophoblast outgrowth, migration, and invasion and mimics events occurring in anchoring villi during the first trimester of gestation. Addition to explant cultures from 5-8 weeks gestation of a monoclonal antibody to endoglin or of antisense endoglin oligonucleotides significantly stimulated trophoblast outgrowth and migration. These responses were specific, as incubation of explants with nonimmune IgG or sense and scrambled oligonucleotides had no effect. Antisense endoglin-induced trophoblast outgrowth and migration were accompanied by cell division of villous-associated trophoblasts within the proximal region of the forming column and by the characteristic switch in integrins observed in anchoring villi in situ. Treatment of villous explants with antibody and antisense oligonucleotides to endoglin also resulted in an increased fibronectin release into the culture medium. The stimulatory effect of antisense endoglin on fibronectin production was overcome by the addition of exogenous TGFbeta2, but not TGFbeta1 and -beta3. These findings suggest that endoglin expression in the transition from polarized to nonpolarized trophoblasts in anchoring villi is necessary for mediation of the inhibitory effect of TGFbeta1 and/or TGFbeta3 on trophoblast differentiation along the invasive pathway.

Antibodies↗
PubMed1995

Interleukin-1 stimulates prostaglandin E production by human trophoblast cells from first and third trimesters.

Prostaglandins (PGs) play a major role during implantation and labor, and their level is regulated by various cytokines. Interleukin-1 (IL-1) is a known mediator of prostaglandin E (PGE) production in various cell types, including endothelial, amniotic, and endometrial cells; however, its role in the regulation of PGE production in the trophoblast cells is yet unknown. As IL-1 and PGE are both known to be synthesized in the human trophoblast cells, we examined the possibility that IL-1 regulates PG production in human trophoblast cells. To this end, use was made of first and third trimester trophoblast cells, obtained from first trimester terminations of pregnancies and elective cesarean sections. The trophoblast cells were separated by trypsin degradation and fractionation on Percoll gradients, and cultured for 18 h under serum-free conditions in the absence or presence of IL-1 (10 ng/mL). IL-1 induced a 5-fold increase in PGE production, a response that was cell density, time, and dose dependent. IL-1-induced PGE biosynthesis was prevented in the presence of either IL-1 receptor antagonist or the soluble IL-1 receptor, suggesting a receptor-mediated response. Significantly, de novo production of PGE by trophoblast cells in the absence of IL-1 was also markedly (50%) reduced by either the IL-1 receptor antagonist or the soluble IL-1 receptor, further supporting the notion that IL-1 is involved in PGE synthesis even under basal conditions. Transforming growth factor-beta 1, a putative modulator of the effects of IL-1, significantly attenuated IL-1-stimulated PGE production, supporting the possibility that transforming growth factor-beta 1 may serve as a regulator of the effects of IL-1 in trophoblast cells. These observations suggest a pivotal role of IL-1 in the regulation of PGE economy by trophoblast cells. As trophoblast cells are in intimate contact with maternal cells, understanding the regulation of PGE levels may explain crucial processes at the feto-maternal interface, including implantation of the developing blastocyst, immunosurveilance, and the initiation of labor.

Cell Count↗