Interleukin-1β costimulates interferon-γ production by human natural killer cells

Natural killer (NK) cells are an early source of immunoregulatory cytokines during the innate immune response to viruses, bacteria, and parasites. NK cells provide requisite IFN-γ to monocytes for the elimination of obligate intracellular pathogens. IL-1β is a pro-inflammatory cytokine produced by monocytes (i.e. a monokine) during the early immune response to infection, but its role in promoting human NK cell IFN-γ production is unknown. The current study examines the ability of the monokine IL-1β, plus IL-12, to costimulate IFN-γ production by resting CD56^bright and CD56^dim human NK cell subsets. CD56^bright NK cells stimulated with IL-1β plus IL-12 produced abundant IFN-γ protein, while little IFN-γ was produced in identical cultures of CD56^dim cells. In addition, upon activation with IL-1β, CD56^bright NK cells exhibited considerably greater phosphorylation of extracellular signal-regulated kinases p42/44 as compared to CD56^dim NK cells. Quantitative PCR analysis showed brisk induction of IFN-γ gene expression following costimulation with IL-1β plus IL-12 in CD56^bright NK cells, but intracellular flow cytometry revealed that only a fraction (42±2.3%) of CD56^bright NK cells account for this high IFN-γ production. These data suggest that the monokine IL-1β is a potent costimulus of IFN-γ production by a subset of NK cells following infectious insult.