Differentiation-induced post-transcriptional control of B7-H1 in human trophoblast cells.
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 4h 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-gamma. 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.
Holets
L M
LM
Department of Anatomy and Cell Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Carletti
M Z
MZ
Kshirsagar
S K
SK
Christenson
L K
LK
Petroff
M G
MG
D000328:Adult; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D060890:B7-H1 Antigen; D002454:Cell Differentiation / Q000502:physiology*; D002459:Cell Fusion; D002469:Cell Separation; D002478:Cells, Cultured; D002824:Chorionic Villi; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D011247:Pregnancy; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism; D055815:Young Adult
D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D007371:Interferon-gamma