Recombinant HLA-G5 and -G6 drive U937 myelomonocytic cell production of TGF-beta1.
Throughout human pregnancy, activated maternal macrophages producing anti-inflammatory cytokines comprise a stable cell population in the uterus. This organ is also massively infiltrated with semiallogeneic, placenta-derived, invasive cytotrophoblast cells, which produce membrane and soluble isoforms of human leukocyte antigen (HLA)-G. Here, we investigated the possibility that two soluble isoforms of HLA-G, HLA-G5 and -G6, program macrophage production of cytokines. The model system consisted of human U937 myelomonocytic cells treated with phorbol 12-myristate 13-acetate (PMA) and interferon-gamma (IFN-gamma), which induced differentiation and activation but did not affect their viability or decrease their expression of the two inhibitory immunoglobulin-like transcript (ILT) receptors for HLA-G, ILT2 and ILT4. Exposure of the PMA/IFN-gamma-treated U937 cells to increasing concentrations of recombinant HLA-G5 or -G6 (rG5 and rG6) stimulated effects common to the two isoforms. High doses of both significantly decreased interleukin (IL)-10 and dramatically increased transforming growth factor-beta1. Differential effectiveness between the isoforms was demonstrated in dose-response studies, as was differential binding to ILT2 and ILT4 in receptor-blocking studies. No effects on production of IL-4, IL-1 receptor antagonist, IL-15, tumor necrosis factor alpha, IL-1beta, or IL-6 were observed. Collectively, the results are consistent with the postulate that environmental programming of decidual macrophages may be dictated in part by their proximity to soluble HLA-G-producing fetal cytotrophoblast cells.
Departments of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Ramsey H
RH
McIntire
Pedro J
PJ
Morales
Margaret G
MG
Petroff
Marco
M
Colonna
Joan S
JS
Hunt
D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005260:Female; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D053773:Transforming Growth Factor beta1; D020298:U937 Cells
D015703:Antigens, CD; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C105299:LILRB1 protein, human; C491341:LILRB2 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate