Combined Stimulation with Interleukin-18 and Interleukin-12 Potently Induces Interleukin-8 Production by Natural Killer Cells

J Innate Immun. 2017;9(5):511-525. doi: 10.1159/000477172. Epub 2017 Jun 21.


The combination of interleukin (IL)-18 and IL-12 (IL-18+IL-12) potently stimulates natural killer (NK) cells, triggering an innate immune response to infections and cancers. Strategies exploiting the effects of IL-18+IL-12 have shown promise for cancer immunotherapy. However, studies have primarily characterized the NK cell response to IL-18+IL-12 in terms of interferon (IFN)-γ production, with little focus on other cytokines produced. IL-8 plays a critical role in activating and recruiting immune cells, but it also has tumor-promoting functions. IL-8 is classically produced by regulatory NK cells; however, cytotoxic NK cells do not typically produce IL-8. In this study, we uncover that stimulation with IL-18+IL-12 induces high levels of IL-8 production by ex vivo expanded and freshly isolated NK cells and NK cells in peripheral blood mononuclear cells. We further report that tumor necrosis factor (TNF)-α, produced by NK cells following IL-18+IL-12 stimulation, regulates IL-8 production. The IL-8 produced is in turn required for maximal IFN-γ and TNF-α production. These findings may have important implications for the immune response to infections and cancer immunotherapies. This study broadens our understanding of NK cell function and IL-18+IL-12 synergy by uncovering an unprecedented ability of IL-18+IL-12-activated peripheral blood NK cells to produce elevated levels of IL-8 and identifying the requirement for intermediates induced by IL-18+IL-12 for maximal cytokine production following stimulation.

Keywords: Cytokines; Immunotherapy; Innate immunity; Natural killer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols
  • Cancer Vaccines / immunology*
  • Cells, Cultured
  • Cytotoxicity, Immunologic
  • Drug Synergism
  • Humans
  • Immunization
  • Immunotherapy, Adoptive / methods*
  • Interferon-gamma / metabolism
  • Interleukin-12 / pharmacology*
  • Interleukin-18 / pharmacology*
  • Interleukin-8 / metabolism*
  • Killer Cells, Natural / immunology*
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Tumor Necrosis Factor-alpha / metabolism


  • Cancer Vaccines
  • Interleukin-18
  • Interleukin-8
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interferon-gamma