Tumour necrosis factor-α impairs chorionic gonadotrophin ß-subunit expression and cell fusion of human villous cytotrophoblast

Leisser, Christina; Saleh, Leila; Haider, Sandra; Husslein, H; Sonderegger, Stefan Eugen; Knöfler, Martin

doi:10.1093/molehr/gal066

Cited by 68 publications

(48 citation statements)

References 59 publications

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“…[45][46][47] In the present study, TNF-α at concentrations of 1 and 10 ng/ml were used, which are in fact higher than observed in vivo levels. However, used concentrations are in line with a number of other placental explant studies 9,10,48 and may reflect microenvironmental concentrations in the intervillous space, where autocrine/paracrine acting TNF-α concentrations may be higher than systemic levels.…”

Section: Discussionsupporting

confidence: 73%

“…7,8 Elevated TNF-α levels during distressed pregnancies have been suggested to affect trophoblast biology including migratory activity, syncytialization, and endocrine function. 9,10 Moreover, elevated TNF-α may influence the fetal-maternal cross-talk by provoking a shift in the secretory profile of placenta-derived immunemodulating factors, which in turn influences the activity of maternal immune cells. Indeed, trophoblast-derived factors can induce differentiation of peripheral blood monocytes into macrophages 11 and enhance recruitment and differentiation of inducible regulatory T cells (Tregs).…”

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confidence: 99%

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TNF-α alters the inflammatory secretion profile of human first trimester placenta

Siwetz

Blaschitz

El‐Heliebi

et al. 2016

Laboratory Investigation

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Implantation and subsequent placental development depend on a well-orchestrated interaction between fetal and maternal tissues, involving a fine balanced synergistic cross-talk of inflammatory and immune-modulating factors. Tumor necrosis factor (TNF)-α has been increasingly recognized as pivotal factor for successful pregnancy, although high maternal TNF-α levels are associated with a number of adverse pregnancy conditions including gestational hypertension and gestational diabetes mellitus. This study describes effects of exogenously applied TNF-α, mimicking increased maternal TNF-α levels, on the secretion profile of inflammation associated factors in human first trimester villous placenta. Conditioned culture media from first trimester villous placental explants were analyzed by inflammation antibody arrays and ELISA after 48 h culture in the presence or absence of TNF-α. Inflammation antibody arrays identified interleukin (IL)-6, IL-8, chemokine (C-C motif) ligand 2 (CCL2), CCL4, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as the most abundantly secreted inflammation-associated factors under basal culture conditions. In the presence of TNF-α, secretion of GM-CSF, CCL5, and IL-10 increased, whereas IL-4 and macrophage CSF levels decreased compared with controls. ELISA analysis verified antibody arrays by showing significantly increased synthesis and release of GM-CSF and CCL5 by placental explants in response to TNF-α. Immunohistochemistry localized GM-CSF in the villous trophoblast compartment, whereas CCL5 was detected in maternal platelets adhering to perivillous fibrin deposits on the villous surface. mRNA-based in situ padlock probe approach localized GM-CSF and CCL5 transcripts in the villous trophoblast layer and the villous stroma. Results from this study suggest that the inflammatory secretion profile of human first trimester placenta shifts towards increased levels of GM-CSF, CCL5, and IL10 in response to elevated maternal TNF-α levels, whereas IL-6 and IL-8 remain unaffected. This shift may represent a protective mechanism by human first trimester villous placenta to sustain trophoblast function and dampen inflammatory processes in the intervillous space. Implantation and subsequent placenta development are mandatory steps for successful human pregnancy and depend on a well-orchestrated interaction between fetal and maternal tissues. Fetal-maternal interaction involves a fine balanced synergistic cross-talk of inflammaory and immune-modulating factors to allow maternal immune adaption and tolerance of the semiallogeneic fetus at the one hand, whereas maternal immune functions need to be maintained to fight off infections on the other hand. Various concepts and paradigms have been suggested trying to explain how the maternal immune system is modulated to guarantee a viable pregnancy. One of the proposed paradigms is based on studies by Wegmann et al, 1 describing a shift from an inflammatory T-helper 1 (Th1) cytokine profile to a rather anti-inflammatory T-helper 2 (Th2) profile. ...

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

TNF-α alters the inflammatory secretion profile of human first trimester placenta

Siwetz

Blaschitz

El‐Heliebi

et al. 2016

Laboratory Investigation

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“…In preeclampsia, TNFα, together with IFNγ, has been shown to cause apoptosis of cultured cytoblasts and syncytiotrophoblasts, together with impairment of syncytialization, especially under hypoxic conditions in term placenta. 163 In vitro studies have shown that the combination of TNFα and IFNγ inhibit first trimester EVT invasion due to increased apoptosis and reduced proliferation of EVT cells and reduced pro-MMP-2 secretion. 164 Hypoxia/ re-oxygenation leading to placental oxidative stress is a potent inducer of TNFα secretion by villous explants.…”

Section: Tnfα and Preeclampsiamentioning

confidence: 99%

The role of tumor necrosis factor-receptors in pregnancy with normal and adverse outcome

Calleja‐Agius¹,

Muttukrishna²,

Jauniaux³

2012

IJICMR

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“…Inhibiting action EGF (Alsat et al, 1993;Morrish et al, 1987) hCG (Cronier et al, 1994;Shi et al, 1993) cAMP (Cronier et al, 1997b;Keryer et al, 1998) GM-CSF (Garcia-Lloret et al, 1994) Macrophages and macrophage-conditionned media (Cervar et al, 1999;Khan et al, 2000) Dexamethasone (Cronier et al, 1998) Estradiol (Cronier et al, 1999b) TGF-β1 (Cronier et al, 1997a;Morrish et al, 1991) LIF (Nachtigall et al, 1996) Hypoxia, SOD-1 (Alsat et al, 1996;Frendo et al, 2001;Frendo et al, 2000a;Levy et al, 2000) Endothelin (Cronier et al, 1999a) 15ΔPGJ2 (Levy et al, 2000) TNFα (Leisser et al, 2006) (Keryer et al, 1998) and also elevate mRNA levels of syncytin1 in cultured trophoblasts (Frendo et al, 2003b). Interestingly syncytin 1 was shown to be a target gene of GCMa, a placenta specific transcription factor that is required for placental development in mouse (Schreiber et al, 2000).…”

Section: Stimulation Actionmentioning

confidence: 99%

Trisomy 21- affected placentas highlight prerequisite factors for human trophoblast fusion and differentiation

Malassiné¹,

Frendo²,

Évain-Brion³

2010

Int. J. Dev. Biol.

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Trophoblastic cell fusion is one essential step of the human trophoblast differentiation pathway and is a multifactorial and dynamic process finely regulated and still poorly known. Disturbances of syncytiotrophoblast formation are observed in numerous pathological clinical conditions such as preeclampsia, intrauterine growth retardation and trisomy 21. In this review, we summarize current knowledge of the different membrane proteins directly involved in trophoblastic cell fusion, which we identified by using the physiological model of primary culture of villous trophoblastic cells. Connexin 43 and gap junctional intercellular communication point to the role of molecular exchanges through connexin channels preceding membrane fusion. Zona occludens-1, which can interact with connexin 43, is also directly involved in trophoblast fusion. The recently identified fusogenic membrane retroviral envelop glycoproteins syncytin 1 (encoded by the HERV-W gene) and syncytin 2 (encoded by the FRD gene) and their receptors are major factors involved in human placental development . We describe the increasing number of factors promoting or inhibiting trophoblast fusion and differentiation and emphasize the role of human chorionic gonadotropin (hCG) and its receptor. Indeed, in trisomy 21 the dynamic process leading to membrane fusion is impaired due to an abnormal hCG signaling. This abnormal trophoblast fusion and differentiation in trisomy 21-affected placenta is reversible in vitro. Trisomy 21 trophoblastic cell culture may therefore be useful to identify the possible large number of prerequisite factors involved in trophoblast fusion, the limiting step of trophoblast differentiation.KEY WORDS: connexin 43, syncytin, hCG, human placenta In the human placenta, the trophoblast differentiates along two major pathways both critical for normal placental functions (Benirschke and Kaufmann, 2000). In the extravillous trophoblast invasive pathway, the cytotrophoblastic cells of the anchoring villi in contact with the uterus wall proliferate, detach from the basement membrane and aggregate into multilayered columns of nonpolarized cells that invade the uterus wall (Fig.1). These cells, which compose the extravillous cytotrophoblast (ECT), invade the endometrium, the first third of the myometrium and the associated spiral arterioles. In the villous trophoblast pathway, the cytotrophoblastic cells (CT) of the floating villi proliferate, differentiate and fuse to form a syncytiotrophoblast (ST) that covers the entire surface of the villi (Fig.1). The syncytiotrophoblast layer plays a major role throughout pregnancy, since it is the site of numerous placental functions, including ion and nutrient exchange and the synthesis of steroid and peptide hormones required for fetal growth and development (Eaton and Contractor, Int. J. Dev. Biol. 54: 475-482 (2010)

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Tumour necrosis factor-α impairs chorionic gonadotrophin ß-subunit expression and cell fusion of human villous cytotrophoblast

Cited by 68 publications

References 59 publications

TNF-α alters the inflammatory secretion profile of human first trimester placenta

TNF-α alters the inflammatory secretion profile of human first trimester placenta

The role of tumor necrosis factor-receptors in pregnancy with normal and adverse outcome

Trisomy 21- affected placentas highlight prerequisite factors for human trophoblast fusion and differentiation

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