Induction of cytolytic activity and interferon-gamma production in murine natural killer cells by polymyxins B and E

Natural killer (NK) cells are the primary effector cells of the innate immune system and have well-established roles in tumor rejection and resistance to viruses, bacteria and certain parasites. There is a need for more specific immune modulators of NK cell activity that tack the wide-ranging side effects of NK cell-stimulatory interleukins. The polycationic antibiotic polymyxin B (PMB) has been shown to have a unique ability to enhance activities of some immune cells, independent of its antibiotic properties. Here we report that both PMB and its analog potymyxin E (PME) markedly enhanced the activity of NK cells enriched from the murine spleen. Maximal activation of NK cell activity was obtained after 24 h of incubation with PMB at a dose of 300 mu g/ml. PMB nonapeptide, one of the two PMB domains, and PME methanesulfonate, the negatively charged derivative of PME, had little effect on NK cell activity. PMB induced interferon (IFN)-gamma and tumor necrosis factor-a production in NK cells. Proliferation of NK cells in vitro was significantly stimulated by being incubated with PMB. Administration of PMB to mice for 7 consecutive days stimulated splenic NK cell activity and increased NK cell populations in the spleen. These results suggest that the polycationic antibiotics PMB and PME may up-regulate innate and adaptive immune responses by induction of NK cell activity and IFN-gamma production.