IL-18 is present at the maternal-fetal interface and enhances cytotoxic activity of decidual lymphocytes.

PROBLEM: Perforin expressing uterine natural killer (uNK) cells are under complex cytokine influence. The aim of the study was to investigate the presence and role of interleukin (IL)-18 on NK cytolytic potential at maternal-fetal (M-F) interface. METHOD OF STUDY: Peripheral blood cells and decidual tissue were obtained from elective pregnancy termination of normal human 6-10-week-old pregnancies. Perforin expression and cytolytic activity of peripheral blood (PBL) and decidual lymphocytes (DL) were analyzed by flow cytometry. IL-18 positive decidual adherent cells (DAC) were detected by the same method. Interleukin-18 and IL-18 receptor (IL-18R) expression on the trophoblastic cells was detected by immunohistology using biotinylated anti-IL-18 and IL-18R monoclonal antibodies. RESULTS: The IL-18 added in a dose of 10 ng/mL up-regulates perforin expression and cytolytic activity of DL. Simultaneous stimulation with IL-18 and IL-12 enhanced DL cytolytic activity, while IL-18 combined with IL-10 or IL-15 did not show this effect. Cytolytic activity of PBL was up-regulated by IL-18 as well, and this effect was enhanced by the addition of IL-12 and IL-15. Interleukin-18 did not affect perforin-protein expression in cultured PBL. Approximately 20% of DAC were IL-18 positive and these cells were mostly human leukocyte antigen (HLA)-DR negative. IL-18R positive cells were found on syncytiotrophoblast cell layer, interstitial tissue cells of villi and fetal blood cells. There was no detectable IL-18 staining on trophoblast cell layer on villi, but strong staining of fetal blood cells in villous vessels. CONCLUSION: These are first results showing IL-18R expression, but not IL-18 expression on villous trophoblastic cells, as well as enhancement of perforin expression and NK cytolytic potential of DL under the influence of IL-18. IL-18 in concert with other cytokines and hormones could play an important role in the regulation of cytolytic potential of first trimester pregnancy decidual and peripheral blood NK cells.

Progesterone induced blocking factor (PIBF) mediates progesterone induced suppression of decidual lymphocyte cytotoxicity.

PROBLEM: Progesterone induced blocking factor (PIBF) is a mediator of progesterone that blocks peripheral blood lytic natural killer (NK) activity. Progesterone or PIBF stimulated decidual macrophages block up-regulation of perforin expression in decidual lymphocytes (DL). Therefore, we investigated whether progesterone regulates cytotoxicity of DL. METHOD OD STUDY: Decidual mononuclear cells were cultured with progesterone. PIBF, progesterone and anti-PIBF antibody or in the medium only. Cytolytic activity of non-adherent DL was measured by PKH-26 (red) 2 hr cytolytic assay and flow cytometry. Perforin positive DL were detected by immunofluorescency and PIBF-positive cells by immunohistology. RESULTS: Progesterone and PIBF, in a dose-dependent manner decreased cytotoxicity of DL against K-562 targets, and perforin egzocytosys was blocked. Anti-PIBF antibodies reversed the progesterone mediated reduction in cytolytic activity of DL. PIBF positive cells were found in first trimester pregnancy decidua. CONCLUSION: The results indicate possible role for PIBF, as a mediator of progesterone in regulation of DL cytolytic activity at the maternal-foetal (M-F) interface.