Critical Contribution of IFN-gamma and NK Cells, but Not Perforin-Mediated Cytotoxicity, to Anti-Metastatic Effect of Alpha-Galactosylceramide

Eur J Immunol. 2001 Jun;31(6):1720-7.

Abstract

The glycolipid alpha -galactosylceramide (alpha -GalCer), which is presented by CD1d and specifically activates Valpha 14 NKT cells, exerts a potent anti-metastatic effect when administered in vivo. In this study, we demonstrated that alpha -GalCer administration led to rapid elimination of NKT cells by apoptosis in the liver and spleen, after they produced IFN-gamma and IL-4. In contrast, a more prolonged secretion of IFN-gamma was observed by liver and splenic NK cells after alpha -GalCer administration. Cytotoxic activity of liver mononuclear cells was not augmented 3h after alpha -GalCer administration, but was increased at 24 h when NKT cells were mostly depleted. The alpha -GalCer-induced cytotoxic activity was abolished in IFN-gamma -deficient and NK cell-depleted mice as well as CD1-deficient mice, suggesting that the alpha -Galcer-induced cytotoxicity was mainly mediated by IFN-gamma -activated NK cells. While the alpha -GalCer-induced cytotoxicity in vitro was mostly perforin dependent, anti-metastatic effect of alpha -GalCer was impaired in NK cell-depleted or IFN-gamma -deficient mice but not in perforin-deficient mice. Collectively, these results indicated that the anti-metastatic effect of alpha -GalCer is mainly mediated by NK cells, which are activated secondarily by IFN-gamma produced by alpha -GalCer-activated NKT cells, in a perforin-independent manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / immunology
  • Cytotoxicity, Immunologic / immunology*
  • Galactosylceramides / pharmacology*
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology*
  • Interleukin-4 / biosynthesis
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation
  • Membrane Glycoproteins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / prevention & control*
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • T-Lymphocytes / immunology
  • Time Factors

Substances

  • Antineoplastic Agents
  • Galactosylceramides
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Perforin
  • Interleukin-4
  • Interferon-gamma