Abstract
Natural killer (NK) cells are lymphocytes of the innate immune system that survey the body for stressed and abnormal cells. The integration of signals that they receive through various inhibitory and activating cell surface receptors controls their activation and ability to kill target cells and produce cytokines. In this manner, phenotypically and functionally distinct subsets of NK cells help protect against microbial infections and cancer and shape the adaptive immune response. NK cells can use two different mechanisms to kill their targets, either by cytotoxic granule exocytosis or by induction of death receptor-mediated apoptosis. Death ligands belong to the tumor necrosis factor (TNF) family of ligands. Upon release in close proximity to a cell slated for killing, perforin forms pores in the cell membrane of the target cell through which granzymes and associated molecules can enter and induce apoptosis. NK cells are also involved in antibody-dependent cellular toxicity via the CD16 receptor. In addition to target recognition, NK cells can be also activated by treatment with multiple compounds with stimulatory properties. Apart from interleukins, which belong to the best characterized group of NK cell-stimulating compounds, vitamins and constituents extracted from plants also display the ability to activate NK cells. The current review characterizes several groups of NK cell-activating compounds: vitamins belonging to classes A, B, C, D, and E, polysaccharides, lectins, and a number of phytochemicals used in cancer research, exhibiting stimulatory properties when applied to NK cells. Although in most cases the exact mechanism of action is not known, constituents described in this review seem to be promising candidates for NK cell-stimulating drugs.
Highlights
Natural killer (NK) cells have been identified in the early 1970s due to a series of experiments regarding cytotoxicity in cancer patients [1]
NK cells constitute approximately 10% of lymphocytes circulating in peripheral blood and 90% of this fraction consists of CD56dim CD16bright cells
The results suggest that vitamin B12 displays crucial immunomodulatory effects in the patients, by restoring NK cell activity and normal CD4/CD8 ratio [37]
Summary
Natural killer (NK) cells have been identified in the early 1970s due to a series of experiments regarding cytotoxicity in cancer patients [1]. An indirect recognition mechanism called ADCC (antibody-dependent cellular cytotoxicity) utilizes the ability to express the FcγRIIIa receptor (CD16) by NK cells, which in turn enables antibody-coated target cell detection [4]. The effect of correct target recognition is the activation of killing mechanisms. In death receptor-mediated cytotoxicity, death ligands produced by NK cells attach to the death receptors expressed on the target cell surface, thereby activating the caspase cascade leading to the death of the recognized object. Stimulation effects generally include increased killing of target cells, enhanced IFN-γ and TNFα production, or higher level of degranulation. Many compounds have been identified as activators of protein kinase C (PKC), which plays an important role in the lytic signaling pathway in NK cells; its activation is crucial to maintain NK cell cytotoxicity [16].
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