The anti-tumor effects of IL-12 involve enhanced IFN-gamma production by anti-tumor T cells, their accumulation to tumor sites and in situ IFN-gamma production.
We investigated cellular and molecular mechanisms underlying the anti-tumor effects of IL-12. Intraperitoneal injections of rIL-12 into later stages of tumor-bearing mice induced not only a striking reversal of suppressed IFN-gamma-production by splenic T cells, but also complete regression of s.c. growing tumors. A massive infiltration of lymphoid cells was found following IL-12 treatment. Whereas fresh spleen cells obtained from IL-12-treated tumor-bearing mice failed to express IFN-gamma mRNA, significant levels of IFN-gamma mRNA were detected in the tumor mass of the same mice. The systemic administration of anti-IFN-gamma antibody (Ab) prior to IL-12 injection abrogated the anti-tumor effect of IL-12 although this Ab did neither inhibit accumulation of lymphoid cells to tumor sites nor in situ IFN-gamma expression. Importantly, while high levels of inducible nitric oxide synthase (iNOS) mRNA expression was induced in tumor masses after IL-12 treatment, its expression was completely inhibited by pretreatment with anti-IFN-gamma Ab. Thus, induction of tumor regression by IL-12 is ascribed to a series of events: a striking reversal of suppressed IFN-gamma production by anti-tumor T cells, their accumulation and IFN-gamma production at tumor sites, and manifestation of IFN-gamma activity as exemplified by iNOS expression.
Fujiwara
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Hamaoka
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D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D005260:Female; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology; D018664:Interleukin-12 / Q000627:therapeutic use*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000627:therapeutic use; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic / Q000187:drug effects
D000906:Antibodies; D012333:RNA, Messenger; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase