Published online before print September 30, 2004

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(Journal of Leukocyte Biology. 2004;76:1220-1228.)
© 2004 by Society for Leukocyte Biology

Recombinant HLA-G5 and -G6 drive U937 myelomonocytic cell production of TGF-ß1

Ramsey H. McIntire^*, Pedro J. Morales^*, Margaret G. Petroff^*, Marco Colonna and Joan S. Hunt^*,,1

^* Departments of Anatomy and Cell Biology and
Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas; and
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri

¹ Correspondence: Department of Anatomy and Cell Biology, Mail Stop 3038, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160. E-mail: jhunt{at}kumc.edu

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- (IFN-), 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--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-ß1. 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 , IL-1ß, 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.

Key Words: human • macrophage cytokines • pregnancy immunology

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