Human natural killer cells produce abundant macrophage inflammatory protein-1α in response to monocyte-derived cytokines

Abstract

Once infected by obligate intracellular pathogens, monocytes/macrophages release cytokines that activate natural killer (NK) cells. NK cells in turn produce and secrete monocyte/macrophage activating factors such as interferon-gamma (IFN-γ), which are important in the early control of these infections. Here we demonstrate that human NK cells are potent producers of another monocyte/macrophage-activating factor, macrophage inflammatory protein-1α (MIP-1α). Fresh NK cells produce negligible amounts of MIP-1α after stimulation with the monocyte-derived cytokines IL-12, TNF-α, IL-1β, or IL-10, while stimulation with IL-15 alone results in modest MIP-1α production. Abundant NK cell production of MIP-1α is seen after costimulation with IL-12 and IL-15, and is dose-dependent. Combinations of IL-12 with TNF-α, IL-1β, or IL-10 are substantially less effective inducers of MIP-1α production by NK cells. NK cell MIP-1α mRNA transcripts were detectable within 1 h after costimulation with IL-12 plus IL-15 and steadily increased over 24 h, with a concomitant increase in protein production detectable at 12 h. Resting NK cells constitutively express mRNA transcript for a MIP-1α receptor, and costimulation with IL-12 and IL-15 upregulates its level of expression. Equilibrium binding studies with radioiodinated MIP- 1α were consistent with the induction of a single class of high affinity MIP-1α receptors on NK cells costimulated with IL-12 and IL-15. Addition of exogenous MIP-1α to resting NK cells did not enhance cytokine production, but did increase NK cytotoxic activity. The requirement for IL-15 as a critical cofactor for NK cell production of MIP-1α suggests a potentially unique role for this monocyte-derived cytokine in combination with IL-12. As MIP-1α is known to potentiate the actions of IFN-γ on monocytes and to suppress human immunodeficiency virus replication, the NK cell's production of MIP-1α may be important during the innate immune response to infection.