title: Coadministration of interleukin-18 and interleukin-12 induces a fatal inflammatory response in mice: critical role of natural killer cell interferon-gamma production and STAT-mediated signal transduction.
abstract: The administration of therapeutic doses of recombinant cytokines to patients with malignant disease can be complicated by systemic toxicities, which in their most severe form may present as a systemic inflammatory response. The combination of interleukin (IL)-18 and IL-12 has synergistic antitumor activity in vivo yet has been associated with significant toxicity. The effects of IL-18 plus IL-12 were examined in a murine model, and it was found that the daily, simultaneous administration of IL-18 and IL-12 resulted in systemic inflammation and 100% mortality within 4 to 8 days depending on the strain employed. Mice treated with IL-18 plus IL-12 exhibited unique pathologic findings as well as elevated serum levels of proinflammatory cytokines and acute-phase reactants. The actions of tumor necrosis factor-alpha did not contribute to the observed toxicity, nor did T or B cells. However, toxicity and death from treatment with IL-18 plus IL-12 could be completely abrogated by elimination of natural killer (NK) cells or macrophages. Subsequent studies in genetically altered mice revealed that NK-cell interferon-gamma mediated the fatal toxicity via the signal transducer and activator of transcription pathway of signal transduction. These data may provide insights into methods of ameliorating cytokine-induced shock in humans. (Blood. 2000;96:1465-1473)
authors.affiliation: Departments of Pathology, Medicine, and Surgery, Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. carson-1@medctr.osu.edu
authors.forename: W E
authors.initials: WE
authors.lastname: Carson
authors.forename: J E
authors.initials: JE
authors.lastname: Dierksheide
authors.forename: S
authors.initials: S
authors.lastname: Jabbour
authors.forename: M
authors.initials: M
authors.lastname: Anghelina
authors.forename: P
authors.initials: P
authors.lastname: Bouchard
authors.forename: G
authors.initials: G
authors.lastname: Ku
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: H
authors.initials: H
authors.lastname: Baumann
authors.forename: M H
authors.initials: MH
authors.lastname: Shah
authors.forename: M A
authors.initials: MA
authors.lastname: Cooper
authors.forename: J
authors.initials: J
authors.lastname: Durbin
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000818:Animals; D007249:Inflammation / Q000139:chemically induced* / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology* / Q000633:toxicity*; D020382:Interleukin-18 / Q000276:immunology* / Q000633:toxicity*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000276:immunology
chemical_list: D020382:Interleukin-18; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma