Differentiation-Induced Post-Transcriptional Control of B7-H1 in Human Trophoblast Cells

• Published in: Placenta (Eastbourne) 2009-01, Vol.30 (1), p.48-55
• Main Authors: Holets, L.M, Carletti, M.Z, Kshirsagar, S.K, Christenson, L.K, Petroff, M.G
• Format: Article
• Language: English
• Subjects: Adult; Antigens, CD - genetics; Antigens, CD - immunology; Antigens, CD - metabolism; B7-H1; B7-H1 Antigen; Biological and medical sciences; Cell Differentiation - physiology; Cell Fusion; Cell Separation; Cells, Cultured; Chorionic Villi; Embryology: invertebrates and vertebrates. Teratology; Enzyme Inhibitors - pharmacology; Epidermal growth factor; Epidermal Growth Factor - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Humans; Interferon-gamma; Interferon-gamma - pharmacology; Internal Medicine; mTOR; Obstetrics and Gynecology; PD-1; PD-L1; Phosphatidylinositol 3-kinase; Placenta; Polysomal RNA; Pregnancy; Protein Processing, Post-Translational - drug effects; Protein Processing, Post-Translational - physiology; RNA, Messenger - metabolism; Syncytiotrophoblast; Trophoblast; Trophoblasts - cytology; Trophoblasts - metabolism; Young Adult
• ISSN: 0143-4004; 1532-3102
• DOI: 10.1016/j.placenta.2008.10.001

Abstract Trophoblast expression of immunomodulatory proteins in the human placenta is among the mechanisms that are critical for ensuring lymphocyte tolerance to the semi-allogeneic fetus. High levels of B7-H1 on trophoblast cells together with the known role of this protein in establishment of peripheral tolerance suggest that B7-H1 mediates immunological protection of the placenta during gestation. In this study, we investigated the molecular mechanisms of regulation of B7-H1 in trophoblast cells by epidermal growth factor (EGF), a key regulator of trophoblast cell differentiation. EGF increased B7-H1 protein levels within 24 h and mRNA levels within 4 h of the initiation of treatment; by 24 h B7-H1 mRNA levels were similar between control and EGF-treated cells. Analysis of two different potential promoter regions revealed strong promoter activity in response to IFN-γ. In contrast, no promoter activity could be induced by EGF, suggesting that this cytokine regulates B7-H1 expression post-transcriptionally in trophoblast cells. EGF-induced B7-H1 protein expression was completely blocked in the presence of inhibitors of the PI3Kinase/Akt/mTOR pathway, a pathway known to regulate gene expression at the translational level. Finally, analysis of monosomal and polysomal mRNA fractions of untreated and EGF-treated term trophoblast cells revealed that EGF induces a shift towards the translatable fractions and away from the untranslated fractions. These results highlight a novel mechanism for regulation of B7 family proteins in the placenta.