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Departments of
*
Surgery and
Molecular Genetics and Biochemistry, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213;
Division of Host Defense, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Hyogo, Japan;
§
Fujisaki Institute, Hayashibara Biochemical Laboratories, Okayama, Japan; and
¶
Department of Genetics, Osaka University Medical School, Osaka, Japan
Systemic administration of rIL-18 protein to mice significantly
suppresses the growth of murine tumor cell lines. The antitumor effect
of IL-18 appears to be primarily mediated by asialo GM1+
cells. Since IL-18 enhances Fas ligand (FasL) expression on NK cell
lines, the IL-18 antitumor effects could be mediated by FasL-induced
cross-linking of Fas and subsequent tumor apoptosis. To address this
question, rIL-18 or rIL-12 was administered to animals bearing the
CL8-1 melanoma inoculated intradermally into wild type (wt),
lymphoproliferation gene (lpr) (Fas deficient), or
generalized lymphoproliferative disease gene (gld) (FasL
deficient) mice. Although rIL-12 treatment retained significant
antitumor effects in gld and lpr mice,
those of rIL-18 administration were completely abrogated in
gld but not lpr or wt mice. In vitro
cytotoxicity was significantly enhanced against NK-sensitive YAC-1
cells and CL8-1 cells by rIL-18 administration to wt mice, but not to
gld mice. Furthermore, rIL-18 administration augmented
the cytotoxicity of liver lymphocytes harvested from perforin-deficient
mice, whereas rIL-12 administration did not. Consistent with the role
of this pathway, rIL-18 administration also up-regulates the expression
of FasL mRNA in splenocytes. Lysis of CL8-1 cells induced by
anti-Fas agonistic Ab was enhanced about 1.4-fold by IFN-
, a
cytokine that is induced by IL-18 in vitro and in vivo. We conclude
that the antitumor effect of IL-18 is exerted predominantly through a
Fas-dependent pathway. The perforin pathway, however, appears to be the
predominant cytolytic pathway mediating IL-12 antitumor
effects.
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