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Departments of
* Microbiology and
Pediatrics, National Defense Medical College, Tokorozawa, Japan;
Pharmaceutical Research Laboratory, Kirin Brewery, Takasaki, Japan; and
Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan
We recently reported that the direct antitumor effectors in the
liver induced by 
-galactosylceramide (-GalCer) are NK cells that
are activated by the IFN-
produced from NK1.1 Ag+ T
cells (NKT cells) specifically stimulated with -GalCer,
whereas NKT cells cause hepatocyte injury through the Fas-Fas ligand
pathway. In the present study, we investigated how mouse age affects
the -GalCer-induced effect using young (6-wk-old), middle-aged
(30-wk-old), and old (75-wk-old) mice. The serum IFN- and IL-4
concentrations as well as alanine aminotransferase levels after the
-GalCer injection increased in an age-dependent manner. An
-GalCer injection also induced an age-dependent increase in the Fas
ligand expression on liver NKT cells. Under the stimulus of -GalCer
in vitro, the liver mononuclear cells from old and middle-aged mice
showed vigorous proliferation, remarkable antitumor cytotoxicity, and
enhanced production of both IFN- and IL-4 in comparison to those of
young mice, all of which were mediated mainly by NK1.1+
cells. Furthermore, liver mononuclear cells from old mice stimulated
with -GalCer showed a more potent Fas-Fas ligand-mediated
cytotoxicity against primary cultured hepatocytes than did those from
young mice. Most -GalCer-injected old mice, but no young mice, died,
while anti-IFN- Ab pretreatment completely inhibited mouse
mortality. However, -GalCer-induced hepatic injury did not improve
at all by anti-IFN- Ab treatment, and the Fas-ligand expression
of liver NKT cells did not change. Taken together, the synthetic
ligand-mediated function of NKT cells is age-dependently up-regulated,
and the produced IFN- is responsible for -GalCer-induced
antitumor immunity and the mouse mortality, while hepatic injury was
unexpectedly found to be independent of
IFN-.
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