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,
,
Department of Internal Medicine, Divisions of
*
Hematology/Oncology and
Human Cancer Genetics,
Department of Medical Microbiology and Immunology, and the Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210; and
§
PE Applied Biosystems, Foster City, CA 94404
NK cells constitutively express monocyte-derived cytokine
(monokine) receptors and secrete cytokines and chemokines following
monokine stimulation, and are therefore a critical component of the
innate immune response to infection. Here we compared the effects of
three monokines (IL-18, IL-15, and IL-12) on human NK cell cytokine and
chemokine production. IL-18, IL-15, or IL-12 alone did not stimulate
significant cytokine or chemokine production in resting NK cells. The
combination of IL-18 and IL-12 induced extremely high amounts of
IFN-
protein (225 ± 52 ng/ml) and a 1393 ± 643-fold
increase in IFN- gene expression over those in resting NK cells.
IL-15 and IL-12 induced less IFN- protein (24 ± 10 ng/ml;
p < 0.007) and only a 45 ± 19-fold increase
in IFN- gene expression over those in resting NK cells. The
CD56bright NK cell subset produced significantly more
IFN- following IL-18 and IL-12 compared with CD56dim NK
cells (p < 0.008). However, the combination of
IL-15 and IL-12 was significantly more potent than that of IL-18 and
IL-12 for NK cell production of IL-10, macrophage inflammatory
protein-1
, macrophage inflammatory protein-1ß, and TNF- at the
protein and transcript levels. Granulocyte-macrophage CSF was optimally
induced by IL-15 and IL-18. Resting CD56+ NK cells
expressed IL-18R transcript that was up-regulated by IL-12 or IL-15.
Our results show that distinct cytokine and chemokine patterns are
induced in NK cells in response to different costimulatory signals from
these three monokines. This suggests that NK cell cytokine production
may be governed in part by the monokine milieu induced during the early
proinflammatory response to infection and by the subset of NK cells
present at the site of inflammation.
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