title: Endogenous accumulation of IFN-gamma in IFN-gamma-R(-/-) mice increases resistance to B16F10-Nex2 murine melanoma: a model for direct IFN-gamma anti-tumor cytotoxicity in vitro and in vivo.
abstract: Syngeneic IFN-gamma(-/-) and IRF-1(-/-) mice are very sensitive to B16F10-Nex2 murine melanoma cells implanted subcutaneously. In contrast, IFN-gamma-R(-/-) (GRKO) mice are remarkably resistant to tumor development. Only 0-30% of these animals, challenged with a high dose of melanoma cells (5 x 10(5)), developed tumors at a late stage. The hypothesis of interferon gamma (IFN-gamma) accumulation and consequent cytotoxicity to implanted tumor cells was confirmed in vitro and ex vivo. IFN-gamma reduced tumor-cell growth in vitro in 60-81%, added alone or with LPS. Splenocytes and peritoneal macrophages from naïve GRKO mice activated with anti-CD3 and interleukin-12 (IL-12), respectively, accumulated IFN-gamma at levels 10-fold those of the wild-type. Supernatants of IL-12-activated macrophages from GRKO mice were toxic to B16F10-Nex2 cells, an effect reversible by anti-IFN-gamma antibody treatment. IL-12-activated macrophages from iNOS(-/-) mice were still highly cytotoxic to B16F10-Nex2 cells, but IL-12-activated macrophages from IFN-gamma-deficient mice were not inhibitory. In vivo, a single injection of anti-IFN-gamma antibody 18 h after tumor-cell challenge in GRKO mice rendered all animals susceptible to B16F10-Nex2 melanoma development. No tumors developed in the untreated GRKO mice during up to 45 days of observation. This model can be useful in understanding immune responses that involve IFN-gamma as a direct cytotoxic factor.
authors.affiliation: Departamento de Microbiologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Elaine G
authors.initials: EG
authors.lastname: Rodrigues
authors.forename: A S
authors.initials: AS
authors.lastname: Garofalo
authors.forename: Luiz R
authors.initials: LR
authors.lastname: Travassos
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010750:Phosphoproteins / Q000276:immunology; D017471:Receptors, Interferon / Q000235:genetics*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000096743:Interferon gamma Receptor
chemical_list: D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma; D018664:Interleukin-12; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C494258:Irf1 protein, mouse