Laboratoire dHormonologie

Liège, Belgium

Laboratoire dHormonologie

Liège, Belgium

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Frank P.,Medicine University of Berlin | Barrientos G.,Medicine University of Berlin | Tirado-Gonzalez I.,Medicine University of Berlin | Cohen M.,Laboratoire DHormonologie | And 7 more authors.
Reproduction | Year: 2014

Nerve growth factor (NGF), the first identified member of the family of neurotrophins, is thought to play a critical role in the initiation of he decidual response in stress-challenged pregnant mice. However, the contribution of this pathway to physiological events during the stablishment and maintenance of pregnancy remains largely elusive. Using NGF depletion and supplementation strategies alternatively, n this study, we demonstrated that a successful pregnancy is sensitive to disturbances in NGF levels in mice. Treatment with NGF further oosted fetal loss rates in the high-abortion rate CBA/J x DBA/2J mouse model by amplifying a local inflammatory response through ecruitment of NGF-expressing immune cells, increased decidual innervation with substance P+nerve fibres and a Th1 cytokine shift. imilarly, treatment with a NGF-neutralising antibody in BALB/c-mated CBA/J mice, a normal-pregnancy model, also induced abortions ssociated with increased infiltration of tropomyosin kinase receptor A-expressing NK cells to the decidua. Importantly, in neither of the odels, pregnancy loss was associated with defective ovarian function, angiogenesis or placental development.We further demonstrated hat spontaneous abortion in humans is associated with up-regulated synthesis and an aberrant distribution of NGF in placental tissue. hus, a local threshold of NGF expression seems to be necessary to ensure maternal tolerance in healthy pregnancies, but when surpassed ay result in fetal rejection due to exacerbated inflammation.


Tirado-gonzalez I.,Medicine University Berlin | Freitag N.,Medicine University Berlin | Barrientos G.,Medicine University Berlin | Shaikly V.,University of Essex | And 8 more authors.
Molecular Human Reproduction | Year: 2013

Galectin-1 (gal-1) is expressed at the feto-maternal interface and plays a role in regulating the maternal immune response against placental alloantigens, contributing to pregnancy maintenance. Both decidua and placenta contribute to gal-1 expression and may be important for the maternal immune regulation. The expression of gal-1 within the placenta is considered relevant to cell-adhesion and invasion of trophoblasts, but the role of gal-1 in the immune evasion machinery exhibited by trophoblast cells remains to be elucidated. In this study, we analyzed gal-1 expression in preimplantation human embryos and first-trimester decidua-placenta specimens and serum gal-1 levels to investigate the physiological role played by this lectin during pregnancy. The effect on human leukocyte antigen G (HLA-G) expression in response to stimulation or silencing of gal-1 was also determined in the human invasive, proliferative extravillous cytotrophoblast 65 (HIPEC65) cell line. Compared with normal pregnant women, circulating gal-1 levels were significantly decreased in patients who subsequently suffered a miscarriage. Human embryos undergoing preimplantation development expressed gal-1 on the trophectoderm and inner cell mass. Furthermore, our in vitro experiments showed that exogenous gal-1 positively regulated the membrane-bound HLA-G isoforms (HLA-G1 and G2) in HIPEC65 cells, whereas endogenous gal-1 also induced expression of the soluble isoforms (HLA-G5 and -G6). Our results suggest that gal-1 plays a key role in pregnancy maternal immune regulation by modulating HLA-G expression on trophoblast cells. Circulating gal-1 levels could serve as a predictive factor for pregnancy success in early human gestation. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Oral glucose tolerance test (OGTT) has been widely used for the diagnosis of diabetes mellitus, gestational diabetes, impaired glucose tolerance or reactive hypoglycemia. Since almost 10 years, however, it has been proposed to limit the use of this dynamic test, favoring instead the measurement of either fasting plasma glucose or glycated hemoglobin. Nevertheless, almost all recent important studies used OGTT as reference test. In this first article, we will consider the potential interest of OGTT as diagnostic or prognostic test able to evaluate glucose regulation. In a second article, we will describe how to use OGTT to derive indices that quantitatively evaluate insulin secretion and/or insulin sensitivity. © 2010 - Elsevier Masson SAS.


Barrientos G.,University of Buenos Aires | Toro A.,University of Buenos Aires | Moschansky P.,Medicine University | Cohen M.,Laboratoire dHormonologie | And 6 more authors.
Placenta | Year: 2015

Introduction The development of the human haemochorial placenta requires complex regulatory mechanisms to protect invasive trophoblast cells from cytotoxic responses elicited by maternal immune cells. Leptin, the adipocyte derived hormone encoded by the Lep gene, is synthesized by placental trophoblasts and exerts pleiotropic effects on the immune system, including the promotion of inflammation and the activation of T cell responses. Methods To address its possible involvement in the modulation of maternal immune responses during pregnancy, we investigated the effect of leptin on the expression of the class Ib histocompatibility antigen HLA-G as one of the chief immunosuppressive strategies used by trophoblast cells. Results In vitro incubation of the trophoblast derived Swan 71 and JEG-3 cell lines with 25-50 ng/ml recombinant leptin significantly boosted HLA-G mRNA and protein expression, and this effect was abrogated upon pharmacological inhibition of the PI3K-Akt and MEK-Erk signaling pathways. A similar stimulatory effect of leptin was observed in term placental tissue explants, though 10-fold higher doses were required for stimulation. Further, JEG-3 cells treated with a leptin antisense oligodeoxynucleotide displayed decreased HLA-G expression levels, which were partially recovered by addition of stimulating doses of exogenous hormone. Immunofluorescence and qPCR analysis confirmed leptin biosynthesis in placental tissue, further showing that invasive extravillous trophoblast cells were a main source of this hormone during the first trimester of normal pregnancies. Discussion Taken together, our results show that leptin acts as an autocrine/paracrine signal promoting HLA-G expression in placental trophoblasts suggesting an important role in the regulation of immune evasion mechanisms at the fetal maternal interface. © 2015 Elsevier Ltd. All rights reserved.


Oral glucose tolerance test (OGTT) has been widely used for the diagnosis of impaired glucose tolerance, diabetes mellitus and gestational diabetes. Simultaneous measurements of plasma glucose and insulin (or more rarely C-peptide) levels allow to derive indices of insulin secretion and insulin sensitivity that are helpful for the understanding of disturbances in glucose metabolism and, especially, for the prediction of progression from normal glucose tolerance to impaired glucose tolerance or type 2 diabetes. Certain indices, quite simple, may be used in clinical practice ("insulinogenic index" to assess early insulin secretion, Matsuda index to assess insulin sensitivity) while others, more complex (and most often based on modelling procedures), are essentially used in research. The oral disposition index, a recently introduced marker that integrates insulin secretion and insulin sensitivity, raises increasing interest, more particularly for the prediction of type 2 diabetes. © 2010 - Elsevier Masson SAS - Tous droits réservés.


Cohen M.,Laboratoire dHormonologie | Wuillemin C.,Laboratoire dHormonologie | Irion O.,Laboratoire dHormonologie | Bischof P.,Laboratoire dHormonologie
Neuroendocrinology Letters | Year: 2010

OBJECTIVE: Proliferation, migration and invasion of trophoblastic cells into the maternal endometrium are essential steps in human embryo implantation and placentation. Trophoblast invasion is normally limited in time, only during first and early second trimester of pregnancy, and in space, limited to the endometrium and the proximal third of myometrium. This process requires among other factors: the metalloproteinases (MMP) 2 and 9. Shallow trophoblast invasion is associated with pathologies including preeclampsia and fetal growth restriction whereas unlimited invasion is associated with hydatidiform moles and choriocarcinomas. METHODS: In order to understand the role of decidua in this endometrial invasion by trophoblastic cells, we have developed a model of coculture of decidual and cytotrophoblastic cells in which we can evaluate the effect of each partner on the proliferative and invasive properties of the other. RESULTS: Surprisingly, decidual cells secrete highest levels of MMPs, and their invasive potential seems to be increased in presence of cytotrophoblast (CTB). In contrast, invasive properties of CTB are not modified by decidual cells. CONCLUSION: CTB secrete factors that favour invasion whereas decidua seems not to play a major role in regulating CTB invasion in vitro. Moreover, it is interesting to note that decidual cells could have potent invasive capacity which could explain, at least in part, endometriosis. © 2010 Neuroendocrinology Letters.


Delie F.,University of Geneva | Delie F.,University of Lausanne | Petignat P.,University of Geneva | Cohen M.,University of Geneva | Cohen M.,Laboratoire dHormonologie
Targeted Oncology | Year: 2013

Glucose-regulated protein 78, GRP78, is a chaperone protein mainly located in the endoplasmic reticulum (ER) of normal cells. In stress conditions, GRP78 is overexpressed and in different cancer cell types, it is expressed at the cell surface, whereas it stays intracellular in non-cancerous cells. Therefore, it appears as a strategic target to recognize malignant cells. Prostate cancer is one of the most diagnosed cancers in men. The development of castrate resistant tumors and the resistance to chemotherapy frequently occur. The carboxy-terminal ER retention domain is defined by the KDEL amino acid sequence. We developed anti-KDEL functionalized polymeric nanoparticles (NPs) loaded with paclitaxel (Tx) to specifically target prostate cancer cells expressing GRP78. The sensitivity to Tx in different formulations was compared in three prostate cell lines: PNT1B, a normal cell line, PC3, a cancer cell line faintly expressing GRP78 at its surface, and DU145, a cancer cell line expressing GRP78 at its cell surface. Our results show that the targeted formulation significantly increases Tx sensitivity of cell line expressing GRP78 at its surface compared to other treatments suggesting the added value of GRP78 targeted therapy for castrate resistant tumor which expresses GRP78 at its cell surface. © 2012 Springer-Verlag France.


Nguyen G.,The Interdisciplinary Center | Nguyen G.,French National Center for Scientific Research | Blanchard A.,University of Paris Descartes | Blanchard A.,French Institute of Health and Medical Research | And 17 more authors.
Hypertension | Year: 2014

A soluble (pro)renin receptor (sPRR) circulates in plasma and is able to bind renin and prorenin. It is not known whether plasma sPRR concentrations vary with the activity of the renin-angiotensin system. We measured plasma sPRR, renin, prorenin, and aldosterone concentrations in 121 white and 9 black healthy subjects, 40 patients with diabetes mellitus, 41 hypertensive patients with or without renin-angiotensin system blockers, 9 patients with primary aldosteronism, and 10 patients with Gitelman syndrome. Median physiological plasma sPRR concentration was 23.5 ng/mL (interquartile range, 20.9-26.5) under usual uncontrolled sodium diet. sPRR concentration in healthy subjects, unlike renin and prorenin, did not display circadian variation or dependence on age, sex, posture, or hormonal status. sPRR concentrations were ≈25% lower in black than in white subjects, whereas renin concentrations were ≈40% lower. Patients with diabetes mellitus (average renin-high prorenin levels) and with hypertension only (average renin-average prorenin levels) had sPRR concentrations similar to healthy subjects. Renin-angiotensin system blockade was associated with increase of sPRR concentration by ≈12%. sPRR in patients with primary aldosteronism (low renin-low prorenin) and Gitelman syndrome (high renin-high prorenin) were similar and ≈10% higher than in healthy subjects. There was no correlation between sPRR and renin or prorenin. In conclusion, our results show that plasma sPRR concentrations are dependent on ethnicity and independent of renin, prorenin, and aldosterone concentrations in healthy subjects and in patients with contrasted degrees of renin-angiotensin system activity. © 2013 American Heart Association, Inc.


Ribaux P.,Laboratoire dHormonologie | Irion O.,Laboratoire dHormonologie | Cohen M.,Laboratoire dHormonologie
Neuroendocrinology Letters | Year: 2012

OBJECTIVES: During implantation, human trophoblastic cells have to proliferate, migrate and invade pregnant uterus. A natural product of cruciferous vegetables, 3,3′-diindolylmethane (DIM), is known to induce some stress response genes (such as glucose-regulated protein 78 kDa (GRP78)) and to have anti-invasive and pro-apoptotic effects on tumor cells. Therefore, we have investigated the potential effect of DIM on invasive extravillous cytotrophoblasts (evCTBs) cells. MATERIALS AND METHODS: evCTBs were purified from first trimester trophoblasts and cultured in presence or not of DIM for 48h. In order to evaluate invasive properties of cells, they were seeded on collagen-coated insert following boyden chamber principle and matrix metalloproteinases (MMPs) and GRP78 expression was evaluated by qPCR. RESULTS: We showed that DIM decreases (p=0.013) invasive properties of evCTBs. In parallel, we determined that MMP-2, -7 and -9 which are involved in evCTBs invasion and known to be regulated by DIM, are not affected by DIM in evCTBs. In contrast, MMP-1 mRNA is induced (p=0.03) and MMP-12 is decreased (p=0.01) in DIM treated cells. Moreover, DIM treatment does not affect GRP78 mRNA expression in evCTBs. CONCLUSIONS: Collectively, the present results provide evidence that DIM does not impact evenly on evCTBs and cancer cells. © 2012 Neuroendocrinology Letters.


PubMed | Austral University, University of Buenos Aires, Hospital Nacional Profesor Alejandro Posadas, Laboratoire dHormonologie and 2 more.
Type: Journal Article | Journal: Placenta | Year: 2015

The development of the human haemochorial placenta requires complex regulatory mechanisms to protect invasive trophoblast cells from cytotoxic responses elicited by maternal immune cells. Leptin, the adipocyte derived hormone encoded by the Lep gene, is synthesized by placental trophoblasts and exerts pleiotropic effects on the immune system, including the promotion of inflammation and the activation of T cell responses.To address its possible involvement in the modulation of maternal immune responses during pregnancy, we investigated the effect of leptin on the expression of the class Ib histocompatibility antigen HLA-G as one of the chief immunosuppressive strategies used by trophoblast cells.In vitro incubation of the trophoblast derived Swan 71 and JEG-3 cell lines with 25-50 ng/ml recombinant leptin significantly boosted HLA-G mRNA and protein expression, and this effect was abrogated upon pharmacological inhibition of the PI3K-Akt and MEK-Erk signaling pathways. A similar stimulatory effect of leptin was observed in term placental tissue explants, though 10-fold higher doses were required for stimulation. Further, JEG-3 cells treated with a leptin antisense oligodeoxynucleotide displayed decreased HLA-G expression levels, which were partially recovered by addition of stimulating doses of exogenous hormone. Immunofluorescence and qPCR analysis confirmed leptin biosynthesis in placental tissue, further showing that invasive extravillous trophoblast cells were a main source of this hormone during the first trimester of normal pregnancies.Taken together, our results show that leptin acts as an autocrine/paracrine signal promoting HLA-G expression in placental trophoblasts suggesting an important role in the regulation of immune evasion mechanisms at the fetal maternal interface.

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