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Laboratory of Cellular Immunology, Division of Cellular and Gene Therapies, and Divisions of
Cytokine Biology and
Hematologic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852
Human NK cell activity can be augmented in vitro by stimulation
with IL-2 or IL-12, both of which also induce the production of
IFN-
, TNF-
, and granulocyte-macrophage CSF by NK cells. For the
first time, we demonstrate that freshly purified NK cells stimulated
with IL-2 proliferated and produced IL-10 in a dose-dependent manner.
IL-10 mRNA expression, as detected by semiquantitative reverse
transcription-PCR, reached peak levels at 24 h. IL-10 protein was
detectable on day 2 and further increased on days 3 and 6 as measured
by ELISA. However, IL-12 alone induced neither substantial
proliferation nor detectable IL-10 production by fresh NK cells, but it
synergized with IL-2 in inducing IL-10 mRNA expression and protein
synthesis. IL-10 production by activated NK cells was confirmed by
intracytoplasmic cytokine staining by three-color immunofluorescence of
CD16+ and/or CD56+ NK cells with
anti-IL-10 antibody. IL-10 production by NK cells was further
confirmed in the NK-like cell line, YT, which constitutively expressed
IL-10 mRNA and protein. IL-12 alone did not induce NK proliferation,
but it inhibited IL-2-induced proliferation. Neutralization of
endogenously produced IL-10 with anti-IL-10 antibodies did not
overcome the inhibition of IL-2-induced proliferation by IL-12.
Together, these results demonstrate that IL-2 and IL-12 synergize to
induce IL-10 production by human NK cells and that IL-12 inhibits IL-2
induced NK cell proliferation by an IL-10-independent mechanism.
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