Interleukin-12 improves cytotoxicity of natural killer cells via upregulated expression of NKG2D

Hum Immunol. 2008 Aug;69(8):490-500. doi: 10.1016/j.humimm.2008.06.004. Epub 2008 Jul 9.


Natural killer (NK) cells are crucial components of the innate immune system, providing the first line of defense against infectious pathogens and tumors. Interleukin (IL)-12 is an interleukin produced primarily by antigen-presenting cells that play an essential role in the interaction between the innate and adaptive arms of immunity acting upon T and NK cells to generate cytotoxic lymphocytes. In the present study, we explored the effect of IL-12 upregulation on the NK receptor NKG2D and on the promotion of NK cell function. IL-12 enhanced the cytotoxicity of NK cells to different solid and hematological tumor cell lines and promoted interferon-gamma secretion by NK cells. The IL-12-induced cytolytic effect was dependent on the interaction of NKG2D with its ligand, MICA, because blockade of either protein attenuated the effect of IL-12 on NK cytolysis. Reverse transcriptase-polymerase chain reaction and fluorescence-activated cell sorting analyses indicated that IL-12 treatment increased NKG2D transcripts and surface expression in NK cells. Also, IL-12 augmented the expression of cytotoxic effector molecules, TRAIL and perforin, and the phosphorylation of STAT1, STAT4, and ERK1/2, which may also contribute to lysis by NK cells. These results are encouraging for the potential use of IL-12 as part of immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Interleukin-12 / immunology*
  • Interleukin-12 / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • NK Cell Lectin-Like Receptor Subfamily K
  • Perforin / immunology
  • Perforin / metabolism
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism*
  • Receptors, Natural Killer Cell
  • STAT1 Transcription Factor / metabolism
  • STAT4 Transcription Factor / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Up-Regulation


  • Histocompatibility Antigens Class I
  • KLRK1 protein, human
  • MHC class I-related chain A
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT4 Transcription Factor
  • STAT4 protein, human
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Perforin
  • Interleukin-12
  • Interferon-gamma
  • Extracellular Signal-Regulated MAP Kinases