title: Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4.
abstract: 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)-gamma 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-12Rbeta1 and IL-12Rbeta2, 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-gamma 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.
authors.affiliation: 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, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Wang
authors.forename: D A
authors.initials: DA
authors.lastname: Frank
authors.forename: J
authors.initials: J
authors.lastname: Ritz
mesh_terms: D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology*; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology*; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D018123:Receptors, Interleukin / Q000276:immunology*; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D015534:Trans-Activators / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D007376:Interleukin-2; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12