Interferon-gamma and interleukin-2 stimulate production of a soluble factor by L1210 and P815 tumor targets to promote macrophage activation.
Previously it was established that L1210 mouse leukemia and a variety of other tumor cell types produced a soluble factor(s), designated tumor-derived recognition factor (TDRF), which synergized with interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) or lipopolysaccharide (LPS) to promote increased tumor necrosis factor-alpha (TNF-alpha) and nitric oxide synthase (NOS) mRNA synthesis by murine macrophages (M phi). Other work revealed that pretreatment of L1210 tumor targets with IFN-gamma rendered them more susceptible to NO-mediated killing by LPS-activated M phi. Now we have combined these observations to determine if pretreatment of L1210 or P815 tumor targets with IFN-gamma and/or IL-2 would augment production of TDRF to enhance M phi activation. Results confirmed that pretreatment of either L1210 or P815 targets with 200 u/ml of IFN-gamma or 1,000 u/ml of IL-2 significantly increased their susceptibility to M phi-mediated cytotoxicity owing to increased NO production. Similar pretreatment of L1210 targets with suboptimal concentrations of IFN-gamma and IL-2 in combination resulted in additive rather than synergistic augmentation of NO-mediated cytotoxicity by cytotoxic M phi. Pretreatment of L1210 targets with IFN-gamma or IL-2 alone or in combination increased the production of TDRF above constitutive levels as demonstrated by increased production of NO and induction of NOS mRNA expression by cytotoxic M phi. Thus IFN-gamma and/or IL-2 promoted increased TDRF production by tumor targets which in turn promoted M phi generation of tumor cytotoxic NO. It appears that M phi activating cytokines have a dual role in acting on certain tumor targets to augment the process of M phi activation through the increased elicitation of immunopotentiating tumor-derived soluble factor(s).
Jiang
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H
Oklahoma Medical Research Foundation, Noble Centerfor Biomedical Research, Oklahoma City, USA.
Robinson
W E
WE
Leu
R W
RW
D000818:Animals; D016207:Cytokines / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000276:immunology*; D007942:Leukemia, Experimental / Q000276:immunology*; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009363:Neoplasm Proteins / Q000276:immunology; D009569:Nitric Oxide / Q000502:physiology
D016207:Cytokines; D007376:Interleukin-2; D009363:Neoplasm Proteins; D009569:Nitric Oxide; D007371:Interferon-gamma