Inhibitors of intracellular signaling affect the production of soluble endoglin by JEG-3 trophoblast cells upon interaction with NK cells
Background: The cytotoxic activity of natural killer (NK) cells is essential for the proper invasion of trophoblasts into the uterine mucosa. Endoglin (Eng) plays an important role in the interaction between NK cells and trophoblasts by assembling the TGFβ receptor complex. The formation of soluble forms of (s)MICA and (s)MICB can help evade NK cell cytotoxicity. The aim of the study: to assess the interaction between NK-92 line NK cells and JEG-3 trophoblast cells via soluble forms of (s)Eng, sMICA and sMICB, when using a TGFβ-dependent signaling pathway inhibitor and a cyclin-dependent kinase (CDK) 7 inhibitor. Materials and methods: We used NK-92 line cells and JEG-3 line trophoblast cells, the TGFβRI inhibitor LY3200882, and the CDK7 inhibitor THZ1. We incubated cells with LY3200882 or THZ1, and then cultured cells with inducers TNFα, IL-10, IFNγ, TGFβ or trichostatin A (TSA). After 24 hours, we assessed the concentrations of sEng, sMICA, sMICB in the medium. Results: We showed that LY3200882 decreased sEng production in JEG-3 line cells. Cytokines IL-10, IFNγ, and TGFβ abolished the effects of LY3200882 on sEng production by JEG-3 line cells. LY3200882 also induced sMICA formation by NK-92 line cells. THZ1 reduced sEng production by JEG-3 line cells, both in the absence of cytokines and following TNFα, IL-10, IFNγ, and TGFβ stimulation. When co-cultured JEG-3 line cells with NK-92 line cells, THZ1 also lowered sEng levels. In the presence of TSA, JEG-3 cells increased sMICB production. However, after exposure of JEG-3 line cells to THZ1 and TSA, we observed a decrease in sMICB levels. Conclusion: Both the TGFβ-dependent signaling inhibitor and the CDK7 inhibitor influence the interaction of NK-92 line cells with JEG-3 line trophoblast cells, affecting sEng production by JEG-3 line cells. The regulation of sEng formation by trophoblast cells presents new therapeutic avenues for managing reproductive pathologies
Mikhailova VA, Marko ОB, Mkrtchyan ER, et al. Inhibitors of intracellular signaling affect the production of soluble endoglin by JEG-3 trophoblast cells upon interaction with NK cells. Research Results in Biomedicine. 2026;12(3):497-510. DOI: 10.18413/2658-6533-2026-12-3-0-9
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