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Keywords:

  • DNA;
  • innate;
  • adaptive;
  • immunity NK

Abstract

Interferon (IFN) α is a pleiotropic cytokine acting as an antiviral substance, cell growth inhibitor and immunomodulator. To evaluate the therapeutic efficacy and mechanisms of IFNα on hepatic metastasis of tumor cells, we hydrodynamically injected naked plasmid DNA encoding IFNα1 (pCMV-IFNa1) into Balb/cA mice having 2 days hepatic metastasis of CT-26 cells. Single injection of pCMV-IFNa1 efficiently enhanced the natural killer (NK) activity of hepatic mononuclear cells, induced production of IFNγ in serum and led to complete rejection of tumors in the liver. Mice protected from hepatic metastasis by IFNα therapy displayed a tumor-specific cytotoxic T cell response and were resistant to subcutaneous challenge of CT-26 cells. NK cells were critically required for IFNα-mediated rejection of hepatic metastasis, because their depletion by injecting anti-asialo GM1 antibody completely abolished the antimetastatic effect. To find whether NK cells are directly activated by IFNα and are sufficient for the antimetastatic effect, the responses to IFNα were examined in SCID mice lacking T cells, B cells and NKT cells. IFNα completely rejected hepatic metastasis in SCID mice and efficiently activated SCID mononuclear cells, as evidenced by activation of STAT1 and a variety of genes, such as MHC class I, granzyme B, tumor necrosis factor-related apoptosis-inducing ligand and IFNγ, and also enhanced Yac1 lytic ability. Study of IFNγ knockout mice revealed that IFNγ was not necessary for IFNα-mediated NK cell activation and metastasis protection. In conclusion, IFNα efficiently activates both innate and adaptive immune responses, but NK cells are critically required and sufficient for IFNα-mediated initial rejection of hepatic metastasis of microdisseminated tumors. © 2006 Wiley-Liss, Inc.