Enhanced suppression of pulmonary metastasis of malignant melanoma cells by combined administration of alpha-galactosylceramide and interleukin-18.
alpha-Galactosylceramide (alpha-GalCer) shows antitumor effects by activating natural killer (NK) cells indirectly through stimulation of the secretion of cytokines by NKT cells, whereas interleukin (IL)-18 shows antitumor effects by activating NK cells directly. In the present study, we examined the antitumor effect of the combined administration of alpha-GalCer and IL-18. An injection of NK cell-sensitive mouse B16 melanoma cells into a mouse tail vein produced pulmonary metastasis. The daily administration of alpha-GalCer or IL-18 alone for 4 days starting 1 day after the injection of B16 melanoma cells markedly suppressed the number of pulmonary metastatic foci, and their combined administration enhanced the antitumor effect compared with single administration. The antitumor effect of their combined administration was completely abolished by treatment of mice with anti-asialo GM1 serum, which depletes NK cells but not NKT cells. Combined administration of alpha-GalCer and IL-18 enhanced the cytotoxicity of NK cells and increased the number of NK cells in the lung. Analysis of NKT cell-dependent and NK cell-independent secretion of cytokines, to which NK cells can respond, showed that the administration of alpha-GalCer increased the secretion of IL-2, IL-4, interferon-gamma, IL-12, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and IL-10, and the combined administration of alpha-GalCer and IL-18 enhanced the secretion of IL-2, IL-4, interferon-gamma, and granulocyte-macrophage colony-stimulating factor further but only slightly. These results show that IL-18 in combination with alpha-GalCer exerts an antitumor effect on NK cell-sensitive tumors primarily by the direct stimulation of NK cells by IL-18 and the indirect stimulation of NK cells by alpha-GalCer through its activation of NKT cells.
Nishio
Shoji
S
Department of Pathology, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Yamada
Naoko
N
Ohyama
Hideki
H
Yamanegi
Koji
K
Nakasho
Keiji
K
Hata
Masaki
M
Nakamura
Yoshiteru
Y
Fukunaga
Satoru
S
Futani
Hiroyuki
H
Yoshiya
Shinichi
S
Ueda
Haruyasu
H
Taniguchi
Masaru
M
Okamura
Haruki
H
Terada
Nobuyuki
N
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000494:pharmacology; D019409:Interleukin-15 / Q000097:blood / Q000276:immunology; D020382:Interleukin-18 / Q000008:administration & dosage / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL
C487652:2-amino-1-galactopyranosyloxy-3,4-dihydroxyoctadecane; D016207:Cytokines; D005699:Galactosylceramides; D019409:Interleukin-15; D020382:Interleukin-18