title: TRAIL (Apo-2L) and TRAIL receptors in human placentas: implications for immune privilege.
abstract: Mechanisms accounting for protection of the fetal semiallograft from maternal immune cells remain incompletely understood. In other contexts, interactions between TRAIL (TNF-related apoptosis-inducing ligand/Apo-2L) and its receptors kill activated lymphocytes. The purpose of this study was therefore to investigate the potential of the TRAIL/TRAIL-R system to protect the placenta against immune cell attack. Analysis by Northern blotting demonstrated mRNAs encoding TRAIL as well as the four TRAIL receptors (DR4, DR5, DcR1/TRID, DcR2/TRUNDD) in human placentas. Immunohistochemical experiments demonstrated that TRAIL protein is prominent in syncytiotrophoblast, an uninterrupted placental cell layer that is continuously exposed to maternal blood, as well as in macrophage-like placental mesenchymal cells (Hofbauer cells). Studies on cell lines representing trophoblasts (Jar, JEG-3 cells) and macrophages (U937, THP-1 cells) showed that both lineages contained TRAIL mRNA and that steady state levels of transcripts were increased 2- to 11-fold by IFN-gamma. By contrast, cell lineage-specific differences were observed in expression of the TRAIL-R genes. Although all four lines contained mRNA encoding the apoptosis-inducing DR5 receptor, only trophoblast cells contained mRNA encoding the DcR1 decoy receptor and only macrophages contained DcR2 decoy receptor transcripts. DR4 mRNA was present only in THP-1 cells and was the only TRAIL-R transcript increased by IFN-gamma. Cytotoxicity assays revealed that the two trophoblast cell lines were resistant, whereas the two macrophage lines were partially susceptible to killing by rTRAIL. Collectively, the results are consistent with a role for the TRAIL/TRAIL-R system in the establishment of placental immune privilege.
authors.affiliation: Departments ofAnatomy and Cell Biology, Pathology and Laboratory Medicine, and Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Phillips
authors.forename: J
authors.initials: J
authors.lastname: Ni
authors.forename: G
authors.initials: G
authors.lastname: Pan
authors.forename: S M
authors.initials: SM
authors.lastname: Ruben
authors.forename: Y F
authors.initials: YF
authors.lastname: Wei
authors.forename: J L
authors.initials: JL
authors.lastname: Pace
authors.forename: J S
authors.initials: JS
authors.lastname: Hunt
mesh_terms: D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000302:isolation & purification*; D010920:Placenta / Q000276:immunology; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000276:immunology*; D012333:RNA, Messenger / Q000302:isolation & purification; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000302:isolation & purification*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014327:Trophoblasts / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000302:isolation & purification*
chemical_list: D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma