Lipopolysaccharide induces IFN-gamma production in human NK cells

Natural killer (NK) cells have been shown to play a regulatory role in sepsis. According to the current view, NK cells become activated via macrophages or dendritic cells primed by lipopolysaccharide (LPS). Recently, TLR4 gene expression was detected in human NK cells suggesting the possibility of a direct action of LPS on NK cells. In this study, effects of LPS on NK cell cytokine production and cytotoxicity were studied using highly purified human NK cells. LPS was shown to induce IFN-gamma production in the presence of 1152 in NK cell populations containing >98% CD56(+) cells. Surprisingly, in the same experiments LPS decreased NK cell degranulation. No significant expression of markers related to blood dendritic cells, monocytes on or B lymphocytes in the NK cell preparations was observed; the portions of HLA-DRbright, CD14(+) CD3(+), and CD20(+) cells amounted to less than 0.1% within the cell populations. No more than 0.2% of NK cells were shown to be slightly positive for surface TLR4 in our experimental system, although intracellular staining revealed moderate amounts of TLR4 inside the NK cell population. These cells were negative for surface CD14, the receptor participating in LPS recognition byTLR4. Incubation of NK cells with 1152 or/and LPS did not lead to an increase in TLR4 surface expression. TLR4(-)CD56(+) NK cells isolated by cell sorting secreted IFN-gamma in response to LPS. Antibody to TLR4 did not block the LPS-induced increase in IFN-gamma production. We have also shown that R-e-form of LPS lacking outer core oligosaccharide and 0-antigen induces less cytokine production in NK cells than full-length LPS. We speculate that the polysaccharide fragments of LPS molecule may take part in LPS-induced IFN-gamma production by NK cells. Collectively our data suggest the existence of a mechanism of LPS direct action on NK cells distinct from established TLR4-mediated signaling.