Perforin-dependent NK cell cytotoxicity is sufficient for anti-metastatic effect of IL-12.
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.
Kodama
T
T
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Takeda
K
K
Shimozato
O
O
Hayakawa
Y
Y
Atsuta
M
M
Kobayashi
K
K
Ito
M
M
Yagita
H
H
Okumura
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D054353:Perforin; D018664:Interleukin-12; D007371:Interferon-gamma