Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4

Interleukin (IL)-12 plays a critical role in modulating the activities of n atural killer (NK) cells and T lymphocytes, In animal models, IL-12 has pot ent antitumor effects that are likely mediated by its ability to enhance th e cytotoxic activity of NK cells and cytotoxic T lymphocytes, and to induce the production of interferon (IFN)-gamma by NK and T cells. In addition to IL-12, NK cells are responsive to IL-2, and may mediate some of the antitu mor 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 n ot only up-regulates the expression of IL-12R beta 1 and IL-12R beta 2, it also plays an important role in up-regulating and maintaining the expressio n 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 a nd STAT4 are unaffected or decreased by IL-12 or the combination of IL-2 an d 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-gamma production and the killing of target cells. NK cells from canc er patients who received low-dose IL-2 treatment also exhibited increased e xpression of IL-12 receptor chains, suggesting that IL-2 may enhance the re sponse to IL-12 in vivo. These findings provide a molecular framework to un derstand the interaction between IL-2 and IL-12 in NK cells, and suggest st rategies for improving the effectiveness of these cytokines in the immunoth erapy of cancer, (C) 2000 by The American Society of Hematology.