title: In vivo antitumor effects of murine interferon-gamma-inducing factor/interleukin-18 in mice bearing syngeneic Meth A sarcoma malignant ascites.
abstract: Interferon-gamma-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 microg 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 gamma. 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.
authors.affiliation: Fujisaki Institute, Hayashibara Biochemical Laboratories Inc., Okayama, Japan.
authors.forename: M J
authors.initials: MJ
authors.lastname: Micallef
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.forename: S
authors.initials: S
authors.lastname: Kawai
authors.forename: T
authors.initials: T
authors.lastname: Hanaya
authors.forename: K
authors.initials: K
authors.lastname: Kohno
authors.forename: S
authors.initials: S
authors.lastname: Arai
authors.forename: T
authors.initials: T
authors.lastname: Tanimoto
authors.forename: K
authors.initials: K
authors.lastname: Torigoe
authors.forename: M
authors.initials: M
authors.lastname: Fujii
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.forename: M
authors.initials: M
authors.lastname: Kurimoto
mesh_terms: D000818:Animals; D001201:Ascites / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000008:administration & dosage* / Q000276:immunology; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007369:Interferon Inducers / Q000008:administration & dosage* / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology; D020382:Interleukin-18; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines; D007369:Interferon Inducers; D020382:Interleukin-18; D007371:Interferon-gamma