In vivo antitumor effects of murine interferon- γ -inducing factor/interleukin-18 in mice bearing syngeneic Meth A sarcoma malignant ascites |
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Authors: | M J Micallef Kenshi Yoshida Sachiko Kawai Toshiharu Hanaya Keizo Kohno Shigeyuki Arai Tadao Tanimoto Kakuji Torigoe Mitsukiyo Fujii Masao Ikeda Masashi Kurimoto |
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Institution: | (1) Fujisaki Institute, Hayashibara Biochemical Laboratories Inc., Fujisaki 675 – 1, Okayama 702, Japan Tel. (81) 86 276 – 3141; Fax (81) 86 276 – 6885, JP |
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Abstract: | Interferon-γ-inducing factor/interleukin-18 is a novel cytokine that reportedly augments natural killer (NK) activity in
human and mouse peripheral blood mononuclear cell cultures in vitro and has recently been designated IL-18. In this study,
IL-18 exhibited significant antitumor effects in BALB/c mice challenged intraperitoneally (i.p.) with syngeneic Meth A sarcoma
when administered i.p. on days 1, 2 and 3 after challenge. Intravenous (i.v.) administration also induced antitumor effects
in the tumor-bearing mice; however, subcutaneous (s.c.) administration did not. When mice were twice pretreated with 1 μg
IL-18 3 days and 6 h before tumor challenge, all mice survived whereas control mice died within 3 weeks of challenge. Inhibitory
effects on Meth A cell growth in vitro were not observed with either IL-18 or interferon γ. The effects of IL-18 pretreatment
were abrogated by abolition of NK activity after mice had been injected with anti-asialo GM1 antibody 48 h before and, 24
h and 72 h after tumor challenge. Mice pretreated with IL-18 and surviving tumor challenge resisted rechallenge with Meth
A cells but could not reject Ehrlich ascites carcinoma, and spleen cells from the resistant mice, but not control mice, exhibited
cytotoxic activity against Meth A cells in vitro after restimulation with mitomycin C-treated Meth A cells for 5 days. The
effector cells in the spleen cell preparations from resistant mice appear to be CD4+ cells because cytolytic activity was significantly inhibited after depletion of this subset by monoclonal antibodies and
complement. In conclusion, IL-18 exhibits in vivo immunologically (primarily NK) mediated antitumor effects in mice challenged
with syngeneic Meth A sarcoma and induces immunological memory and the generation of cytotoxic CD4+ cells.
Received: 17 September 1996 / Accepted: 8 November 1996 |
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Keywords: | Interleukin-18 Antitumor effect NK cells Immunological memory IFN-γ |
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