Interferon-gamma produced by interleukin-12-activated tumor infiltrating CD8+T cells directly induces apoptosis of mouse hepatocellular carcinoma

J Hepatol. 2006 Nov;45(5):662-72. doi: 10.1016/j.jhep.2006.05.018. Epub 2006 Jul 7.


Background/aims: Interleukin-12 (IL-12), a cytokine with antitumor activity, was examined for the suppressive effect on hepatocellular carcinoma (HCC) in mouse model, and its mechanism of antitumor activity was analyzed.

Methods: Mice implanted with MIH-2 HCC cells were treated with recombinant mouse IL-12 (500 ng/mouse). Involvement of CD4(+), CD8(+), NK cells and interferon (IFN)-gamma on tumor suppression by IL-12 was examined by treatment of mice with each antibody. Interferon-gamma (IFN-gamma) production by tumor infiltrating cells was analyzed by immunofluorescence microscopy and flow cytometric analysis. Signal transduction for apoptosis induction was examined by immunoblot analysis.

Results: The growth of implanted MIH-2 tumors was significantly suppressed by IL-12 and the suppression was inhibited by depletion of CD8(+)T cells. IL-12 treatment caused numerous IFN-gamma-producing CD8(+)T cells to infiltrate into MIH-2 tumors. Antitumor activity of IL-12 was blocked by treating mice with anti-IFN-gamma mAb. CD8(+)T cells from IL-12-treated mice attached to MIH-2 cells and produced IFN-gamma in vitro. Cell attachment might be associated with intercellular adhesion molecule-1 induced by IFN-gamma. In vitro treatment with IFN-gamma induced apoptosis of MIH-2 cells via a mitochondria-dependent pathway.

Conclusions: IL-12 suppressed HCC growth in mouse model. IFN-gamma produced by IL-12-activated tumor-infiltrating CD8(+)T cells directly induced apoptosis of HCC cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • Apoptosis / physiology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Carcinoma, Hepatocellular / immunology*
  • Caspase 9 / metabolism
  • Cytochromes c / metabolism
  • Interferon-gamma / metabolism*
  • Interleukin-12 / pharmacology*
  • Liver Neoplasms / immunology*
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Models, Animal
  • Proto-Oncogene Proteins / metabolism
  • Recombinant Proteins / pharmacology


  • Adjuvants, Immunologic
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Interleukin-12
  • Interferon-gamma
  • Cytochromes c
  • Caspase 9