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Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3183-3190
Interleukin-2 enhances the response of natural killer cells to
interleukin-12 through up-regulation of the interleukin-12 receptor
and STAT4
Kathy S. Wang,
David A. Frank, and
Jerome Ritz
From the Center for Hematologic Oncology, Department of Adult
Oncology, Dana-Farber Cancer Institute, and the Department of Medicine,
Brigham and Women's Hospital, Harvard Medical School, Boston, MA
02115.
Interleukin (IL)-12 plays a critical role in modulating the
activities of natural killer (NK) cells and T lymphocytes. In animal
models, IL-12 has potent antitumor effects that are likely mediated by
its ability to enhance the cytotoxic activity of NK cells and cytotoxic
T lymphocytes, and to induce the production of interferon (IFN)- by
NK and T cells. In addition to IL-12, NK cells are responsive to IL-2,
and may mediate some of the antitumor effects of IL-2. In this study,
we examine the interaction between IL-2 and the signaling events
induced by IL-12 in NK cells. We find that IL-2 not only up-regulates
the expression of IL-12R 1 and IL-12R2, it also plays an important
role in up-regulating and maintaining the expression of STAT4, a
critical STAT protein involved in IL-12 signaling in NK cells. In
contrast to the effects of IL-2 alone, expression of IL-12 receptors
and STAT4 are unaffected or decreased by IL-12 or the combination of
IL-2 and IL-12. Through expression of high levels of IL-12 receptors
and STAT4, IL-2-primed NK cells show enhanced functional responses to
IL-12 as measured by IFN- production and the killing of target
cells. NK cells from cancer patients who received low-dose IL-2
treatment also exhibited increased expression of IL-12 receptor chains,
suggesting that IL-2 may enhance the response to IL-12 in vivo. These
findings provide a molecular framework to understand the interaction
between IL-2 and IL-12 in NK cells, and suggest strategies for
improving the effectiveness of these cytokines in the immunotherapy of cancer.
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