title: Human natural killer cells produce abundant macrophage inflammatory protein-1 alpha 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 interferongamma (IFN-gamma), 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-1 alpha (MIP-1 alpha). Fresh NK cells produce negligible amounts of MIP-1 alpha after stimulation with the monocyte-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 MIP-1 alpha is seen after costimulation with IL-12 and IL-15, and is dose-dependent. Combinations of IL-12, with TNF-alpha, IL-1 beta, or IL-10 are substantially less effective inducers 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 increase in protein production detectable at 12 h. Resting NK cells constitutively express mRNA transcript for a MIP-1 alpha receptor, and costimulation with IL-12 and IL-15 upregulates its level of expression. Equilibrium binding studies with radioiodinated MIP-1 alpha were consistent with the induction of a single class of high affinity MIP-1 alpha receptors on NK cells costimulated with IL-12 and IL-15. Addition of exogenous MIP-1 alpha 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 MIP-1 alpha suggests a potentially unique role for this monocyte-derived cytokine in combination with IL-12. As MIP-1 alpha is known to potentiate the action of 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.
authors.affiliation: Department of Hematologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Bluman
authors.forename: K J
authors.initials: KJ
authors.lastname: Bartynski
authors.forename: B R
authors.initials: BR
authors.lastname: Avalos
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D002460:Cell Line; D054407:Chemokine CCL4; D016207:Cytokines / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D019409:Interleukin-15; D007376:Interleukin-2 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins; D015846:Monokines / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D054407:Chemokine CCL4; D016207:Cytokines; D007375:Interleukin-1; D019409:Interleukin-15; D007376:Interleukin-2; D007378:Interleukins; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha