Mol. Hum. Reprod. Advance Access originally published online on January 29, 2004
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Molecular Human Reproduction, Vol. 10, No. 3, pp. 189-195, 2004
© European Society of Human Reproduction and Embryology 2004
Membrane-bound HLA-G activates proliferation and interferon-
production by uterine natural killer cells
1Department of Blood Transfusion and Transplantation Immunology, 2Department of Gynaecology and Obstetrics, University Medical Centre Nijmegen, Nijmegen and 3Department of Pharmacology, NV Organon, 5342 CC Oss, The Netherlands
4 To whom correspondence should be addressed at: Department of Blood Transfusion and Transplantation Immunology (603), University Medical Centre Nijmegen, P.O.Box 9101, Nijmegen, The Netherlands. e-mail: A.vandermeer{at}abti.umcn.nl
The expression of HLA-G by invading trophoblasts suggests a role for this molecule in embryo implantation. Putative targets for HLA-G are the uterine natural killer cells (uNK) that are abundantly present at the time of implantation. Since NK cells are potent producers of a variety of cytokines, interaction with HLA-G may result in the production of cytokines involved in trophoblast differentiation or tissue remodelling. In the present study we investigated the effect of membrane-bound HLA-G (mHLA-G) on the uterine mononuclear cell population (UMC) as a whole and on uNK cells in particular by measuring proliferation and cytokine production [interferon-
(IFN-)/vascular endothelial growth factor (VEGF)/leukaemia inhibitory factor (LIF)/interleukin-3 (IL-3)]. Uterine cells were isolated from endometrium of non-pregnant women at the time that the endometrium is thought to be receptive to implantation, and then co-cultured with HLA-class I–/HLA-class II+ 721.221 B-LCL cells transfected with mHLA-G. HLA-G suppressed the alloproliferative response of unfractionated UMC to 721.221 cells. Also, IFN- and IL-3 production was strongly reduced. In contrast, purified uNK cells were stimulated by mHLA-G. Proliferation as well as IFN- production was increased after co-culture with mHLA-G transfected 721.221 cells. HLA-G stimulated VEGF production by UMC as well as purified uNK cells. LIF-levels were below the detection level of our enzyme-linked immunosorbent assay. In conclusion, our data show that mHLA-G stimulates proliferation and cytokine production by NK cells, while down-modulating the response of unfractionated UMC.
Key words: Key words: 721.221 cells/cytokine/endometrium/HLA-G/NK cell
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