INTERFERON-GAMMA, AND INTERLEUKIN-2 STIMULATE PRODUCTION OF A SOLUBLEFACTOR 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 tum or-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 nit ric 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-ac tivated 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. Result s 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 thei r susceptibility to M Phi-mediated cytotoxicity owing to increased NO production. Similar pretreatment of L1210 targets with suboptimal conc entrations of IFN-gamma and IL-2 in combination resulted in additive r ather than synergistic augmentation of NO-mediated cytotoxicity by cyt otoxic M Phi. Pretreatment of L1210 targets with IFN-gamma or IL-2 alo ne or in combination increased the production of TDRF above constituti ve 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 prom oted M Phi generation of tumor cytotoxic NO. It appears that M Phi act ivating cytokines have a dual role in acting on certain tumor targets to augment the process of M Phi activation through the increased elici tation of immunopotentiating tumor-derived soluble factor(s).