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Mol. Hum. Reprod. Advance Access published online on November 22, 2006
Molecular Human Reproduction, doi:10.1093/molehr/gal100
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received February 22, 2006
Revised August 28, 2006
Accepted October 20, 2006

Article

Soluble HLA-G promotes Th1-type cytokine production by cytokine-activated uterine and peripheral natural killer cells

A. van der Meer 1 *, H.G.M. Lukassen 2, B. van Cranenbroek 1, E.H. Weiss 3, D.D.M. Braat 4, M.J. van Lierop 2, and I. Joosten 1

1 Department of Bloodtransfusion and Transplantation Immunology, The Netherlands
2 Department of Gynaecology and Obstetrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
3 Biocentrum University Munich, Planegg-Martinsried, Germany, The Netherlands
4 Department of Pharmacology, NV Organon, Oss, The Netherlands

* To whom correspondence should be addressed.
A. van der Meer, E-mail: a.vandermeer{at}abti.umcn.nl


  Abstract

Soluble forms of HLA-G (sHLA-G) have been implicated in immune regulation. Fetal trophoblast cells are a prime source of HLA-G. Hence, an interaction between sHLA-G and uterine lymphocytes in the decidual tissues can easily be envisaged. These lymphocytes, when properly activated, are implicated in successful trophoblast invasion, placental maturation and maintenance of pregnancy. However, so far, no data are available on the effect of sHLA-G on the function and phenotype of these cells. Herein, we used a recombinant sHLA-G construct to determine the effect of sHLA-G on uterine lymphocyte cells present in endometrium at the time that it is optimally receptive to trophoblast invasion. In addition, we ascertained the effect of sHLA-G on peripheral lymphocytes. We found that upon co-culture with sHLA-G, proliferation of unfractionated IL-15-stimulated uterine mononuclear cells (UMCs) was inhibited. However, sHLA-G increased both interferon (IFN)-{gamma} and tumour necrosis factor (TNF)-{alpha} production by these cells. Vascular endothelial growth factor (VEGF) production was reduced. Notably, in contrast to membrane-bound HLA-G, sHLA-G did not affect the natural cytolytic activity of UMCs. Similarly, sHLA-G inhibited proliferation but stimulated pro-inflammatory cytokine production by cytokine-activated, unfractionated peripheral blood mononuclear cells (PBMCs). In addition, we showed that the overall inhibitory effect of sHLA-G on proliferation of the whole cell population could be ascribed to selective inhibition of CD4+ T cells. In contrast, sHLA-G induced proliferation and IFN-{gamma} production by both uterine and peripheral natural killer (NK) cells. In conclusion, our data show that the sHLA-G modulates both UMC and PBMC function. sHLA-G, by promoting IFN-{gamma} production by uterine NK cells, may contribute to vascular remodelling of spiral arteries to allow for successful embryo implantation.

Keywords: NK cells/endometrium/implantation/immune modulation.
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