HUMAN NATURAL-KILLER-CELLS PRODUCE ABUNDANT MACROPHAGE INFLAMMATORY PROTEIN-1 IN RESPONSE TO MONOCYTE-DERIVED CYTOKINES

Once infected by obligate intracellular pathogens, monocytes/macrophag es release cytokines that activate natural killer (NK) cells, NK cells in turn produce and secrete monocyte/macrophage activating factors su ch as interferon-gamma (IFN-gamma), which are important in the early c ontrol of these infections, Here we demonstrate that human NK cells ar e potent producers of another monocyte/macrophage-activating factor, m acrophage inflammatory protein-1 alpha (MIP-1 alpha). Fresh NK cells p roduce negligible amounts of MIP-1 alpha after stimulation with the mo nocyte-derived cytokines IL-12, TNF-alpha, IL-1 beta, or IL-10, while stimulation with IL-15 alone results in modest MIP-1 alpha production, Abundant NK cell production of MIP-1 alpha is seen after costimulatio n with IL-12 and IL-15, and is dose-dependent, Combinations of IL-12 w ith TNF-alpha, IL-1 beta, or IL-10 are substantially less effective in ducers of MIP-1 alpha production by NK cells, NK cell MIP-1 alpha mRNA transcripts were detectable within 1 h after costimulation with IL-12 plus IL-15 and steadily increased over 24 h, with a concomitant incre ase in protein production detectable at 12 h, Resting NK cells constit utively express mRNA transcript for a MIP-1 alpha receptor, and costim ulation with IL-12 and IL-15 upregulates its level of expression. Equi librium binding studies with radioiodinated MIP-1 alpha were consisten t with the induction of a single class of high affinity MIP-1 alpha re ceptors on NK cells costimulated with IL-12 and IL-15, Addition of exo genous MIP-1 alpha to resting NK cells did not enhance cytokine produc tion but did increase NK cytotoxic activity, The requirement for IL-15 as a critical cofactor for NK cell production of MIP-1 alpha suggests a potentially unique role for this monocyte-derived cytokine in combi nation with IL-12. As MIP-1 alpha is known to potentiate the actions o f IFN-gamma on monocytes and to suppress human immunodeficiency virus replication, the NK cell's production of MIP-1 alpha may be important during the innate immune response to infection.