title: TNF-α alters the inflammatory secretion profile of human first trimester placenta.
abstract: 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.
authors.affiliation: Institute of Cell Biology, Histology and Embryology, Medical University Graz, Graz, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Siwetz
authors.affiliation: Institute of Cell Biology, Histology and Embryology, Medical University Graz, Graz, Austria.
authors.forename: Astrid
authors.initials: A
authors.lastname: Blaschitz
authors.affiliation: Institute of Cell Biology, Histology and Embryology, Medical University Graz, Graz, Austria.
authors.forename: Amin
authors.initials: A
authors.lastname: El-Heliebi
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University Graz, Graz, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Hiden
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University Graz, Graz, Austria.
authors.forename: Gernot
authors.initials: G
authors.lastname: Desoye
authors.affiliation: Institute of Cell Biology, Histology and Embryology, Medical University Graz, Graz, Austria.
authors.forename: Berthold
authors.initials: B
authors.lastname: Huppertz
authors.affiliation: Institute of Cell Biology, Histology and Embryology, Medical University Graz, Graz, Austria.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0003-0386-6857
authors.initials: M
authors.lastname: Gauster
mesh_terms: D000328:Adult; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D018836:Inflammation Mediators / Q000378:metabolism*; D010920:Placenta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D046509:Tissue Culture Techniques; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D018946:Chemokine CCL5; D017077:Culture Media, Conditioned; D016207:Cytokines; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor