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- Fock, V, et al.
(författare)
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Macrophage-derived IL-33 is a critical factor for placental growth
- 2013
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Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 191:7, s. 3734-3743
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Tidskriftsartikel (refereegranskat)abstract
- IL-33, the most recently discovered member of the IL-1 superfamily and ligand for the transmembrane form of ST2 (ST2L), has been linked to several human pathologies including rheumatoid arthritis, asthma, and cardiovascular disease. Deregulated levels of soluble ST2, the natural IL-33 inhibitor, have been reported in sera of preeclamptic patients. However, the role of IL-33 during healthy pregnancy remains elusive. In the current study, IL-33 was detected in the culture supernatants of human placental and decidual macrophages, identifying them as a major source of secreted IL-33 in the uteroplacental unit. Because flow cytometry and immunofluorescence stainings revealed membranous ST2L expression on specific trophoblast populations, we hypothesized that IL-33 stimulates trophoblasts in a paracrine manner. Indeed, BrdU incorporation assays revealed that recombinant human IL-33 significantly increased proliferation of primary trophoblasts as well as of villous cytotrophoblasts and cell column trophoblasts in placental explant cultures. These effects were fully abolished upon addition of soluble ST2. Interestingly, Western blot and immunofluorescence analyses demonstrated that IL-33 activates AKT and ERK1/2 in primary trophoblasts and placental explants. Inhibitors against PI3K (LY294002) and MEK1/2 (UO126) efficiently blocked IL-33–induced proliferation in all model systems used. In summary, with IL-33, we define for the first time, to our knowledge, a macrophage-derived regulator of placental growth during early pregnancy.
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- Fock, V, et al.
(författare)
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Neuregulin-1-mediated ErbB2-ErbB3 signalling protects human trophoblasts against apoptosis to preserve differentiation
- 2015
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Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 128:23, s. 4306-4316
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Tidskriftsartikel (refereegranskat)abstract
- During placentation foetal trophoblasts invade deeply into maternal tissue to establish a foeto-maternal circulation. We have previously shown that extravillous trophoblast (EVT) lineage cells express ErbB2/ErbB3, whose potential as oncogenic unit is well established. However, a physiological function of this receptor combination in humans remains a puzzling question. Here we could demonstrate neuregulin (NRG) 1 expression and secretion by human decidual stromal cells. Stimulation of human primary trophoblasts with exogenous NRG1 induced phosphorylation of ErbB2, ErbB3 and related downstream effectors. Co-immunoprecipitation experiments confirmed the formation of ErbB2/ErbB3 dimers upon ligand engagement. Along this line, receptor knockdowns and ErbB3 neutralization strongly diminished NRG1-dependent activation of the signalling unit. Functional studies revealed that NRG1 promotes EVT formation in placental explant cultures. While in the presence of NRG1 basal and camptothecin-induced trophoblast apoptosis was significantly repressed, this effect was abolished upon ErbB3 inhibition. Notably, camptothecin provoked a strong reduction of trophoblast cell columns in size, whereas NRG1-treated explants were refractory to the compound. Together, our findings highlight a novel physiological function of the NRG1/ErbB2/ErbB3 axis in trophoblast survival during human placental development.
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