Nisin is a peptide bacteriocin, grouped under the category of lantibiotics. It is naturally produced by Lactococcus lactis to eliminate other competing gram-positive bacteria from its vicinity. Moreover under certain conditions it is reported to be effective against a broad range of gram-negative bacteria as well. Thus, it has been widely used as a safe food preservative especially in the dairy industry. Because of its wide-scale consumption, its effect on eukaryotic cells should be of great concern. Here we examine the immunomodulatory efficacy of nisin in vitro. MTT-based cytotoxicity assay demonstrated nisin's cytotoxicity on human T-cell lymphoma Jurkat cells, Molt-4 cells and freshly cultured human lymphocytes at over 200 µM concentration (IC(50) 225 µM). The cell death mechanism induced by nisin in all these lymphocyte types was independent of oligonucleosomal DNA fragmentation, as analyzed by agarose gel electrophoresis and comet assay. Additionally, scanning electron microscope and fluorescence microscopy demonstrated the ability of nisin to activate human PMNs in vitro. Nisin-activated neutrophils extruded intact nuclear chromatin to form NETs, well known for neutralization of virulence factors and extermination of bacterial pathogens. Nisin's presence also elevated neutrophil intracellular superoxide levels, normally produced by activated NADPH oxidase and prerequisite to NET formation. These nisin-induced responses in cellular representatives of two separate branches of human immune system-adaptive and innate-although leading to cell death, did not include DNA fragmentation. From these findings, we propose that nisin might trigger similar AICD mechanisms in lymphocytes and neutrophils, different from conventional apoptosis which involves DNA fragmentation.