Activation of natural killer cells in the pathogenesis of preeclampsia

Abstract Background: Preeclampsia (PE) is a serious pregnancy-specific systemic inflammatory disorder. The characteristic pathological abnormality in PE is impaired uterine spiral artery (SA) remodeling. Natural cells (NK) cells have been proposed to play an important role in uterine SA remodeling, particularly in early pregnancy. Still, the definitive role of NK cells in later phases of PE is largely unstudied. In the present study, we investigated the association between NK cells and PE in late human pregnancy. Methods: Collected normal control (n = 18), late-onset (n = 28) and early-onset PE patients peripheral blood and decidua, isolated mononuclear cells, the ratio of NK cells and the level of intracellular cytokines production were evaluated using Flow cytometry. Co-culture first trimester cytotrophoblast cells with conditioned medium (CM) from decidual NK (dNK) cells, evaluated cytotrophoblast cells migration, invasion, NK cytotoxicity and soluble factors secreted by dNK cells. For multiple group comparisons, data were analyzed using one-way analysis of variance with Bonferroni post-testing when the variances were homogeneous or with Tamhane’s T2 post-testing when the variances were not homogeneous. P < 0.05 was considered significant.Results: We found that the numbers of both peripheral blood NK (pNK) cells and dNK cells and intracellular interferon (IFN)-γ, perforin and granzyme B production were significantly higher in PE compared with normal pregnancies at the time of delivery for both early-onset and late-onset disease. dNK cells from PE pregnancies not only killed primary first trimester trophoblast cells in vitro but also inhibited their migration and invasion when compared to normal controls. Using recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-8, IFN-γ and tumor necrosis factor (TNF)-α, and neutralizing Abs against these factors, we demonstrated that GM-CSF and IL-8 in the CM from dNK cells promoted, while IFN-γ and TNF-α inhibited trophoblast cell migration and invasion. Conclusion: Our results suggest that activation of NK cells may play an important role in the pathogenesis of PE in late pregnancy. Elevated local levels of dNK cell-derived IFN-γ and TNF-α and decreased GM-CSF and IL-8 in preeclamptic pregnancies may directly mediate known reductions in trophoblast cell migration and invasion in deciduae from preeclamptic pregnancies.