Perforin-dependent NK cell cytotoxicity is sufficient for anti-metastatic effect of IL-12

Eur J Immunol. 1999 Apr;29(4):1390-6. doi: 10.1002/(SICI)1521-4141(199904)29:04<1390::AID-IMMU1390>3.0.CO;2-C.


IL-12 exerts a potent anti-tumor effect, which is possibly mediated by multiple mechanisms including activation of NK and NKT cells, induction of cytotoxic T lymphocytes, and inhibition of angiogenesis. In the present study, we characterized the cytotoxic effector cells and mechanisms responsible for the anti-metastatic effect of IL-12. Administration of IL-12 had a comparable inhibitory effect on experimental lung metastasis of B16 melanoma cells in wild-type C57BL/6 mice and RAG-2-/- mice that lack T and NKT cells, which was abolished by depletion of NK cells. Cytotoxic activity of liver and splenic mononuclear cells against B16 was induced by IL-12 administration in RAG-2-/- mice at a level comparable to that in wild-type mice, which was also abolished by depletion of NK cells. Moreover, the anti-metastatic effect of IL-12 was abrogated by perforin deficiency, but not by Fas ligand deficiency, in association with a lack of IL-12-induced cytotoxic activity of liver and splenic mononuclear cells against B16. These results suggest that perforin-dependent cytotoxicity of IL-12-activated NK cells is sufficient for the anti-metastatic effect of IL-12.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cytotoxicity, Immunologic*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Interferon-gamma / blood
  • Interleukin-12 / pharmacology*
  • Killer Cells, Natural / immunology*
  • Male
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / prevention & control*
  • Perforin
  • Pore Forming Cytotoxic Proteins


  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Rag2 protein, mouse
  • V(D)J recombination activating protein 2
  • Perforin
  • Interleukin-12
  • Interferon-gamma