In previous studies we showed that tumor-associated macrophages isolated from murine mammary tumors are mutagenic to bacteria and mammalian cells and thus may contribute to tumor progression. We reported previously, and confirm here, that inflammatory macrophages induce DNA strand breaks in cultured mammary tumor cells co-incubated at a 1:1 ratio for 1 h. This activity is prevented by inhibitors of arachidonate metabolism or the removal of H2O2 with catalase. In the present study, we show that two antibodies to recombinant murine tumor necrosis factor alpha (rMuTNFa)--a hamster monoclonal antibody (TN3-19.12) and a rabbit polyclonal antibody (Genzyme)--partially protect tumor cells from DNA strand breaks induced by elicited but not resident peritoneal macrophages. Antibody protection was reversed upon the addition of excess exogenous rMuTNFa. Purified rMuTNFa alone was unable to induce DNA strand breaks in the absence of macrophages, indicating that TNFa is necessary but not sufficient to mediate damage. Tumor target cells were completely resistant to the cytotoxic effects of rMuTNFa in the absence of actinomycin D and relatively resistant (in comparison to WEHI 164 clone 13 cells) in its presence. The incomplete protection seen with either catalase or anti-TNF suggests that macrophage-released TNFa, in the presence of other factors, induces non-cytotoxic DNA effects in tumor cells.
We have described a high-affinity receptor for prostaglandin E2 (PGE2) present on metastatic murine mammary tumor cells. Pharmacologic antagonism of this receptor increases metastatic potential. In the present study, we have asked whether the binding activity of PGE on tumor target cells plays a role in natural killer (NK)-target cell interactions. We have used three unrelated PGE-receptor antagonists, SC19220, LEO101, and AH6809, to show inhibition of [3H]PGE2 binding to YAC-1 cells and inhibition of PGE2-mediated elevation of intracellular cyclic AMP (cAMP). Addition of any of these three receptor antagonists to standard 4-h 51Cr-release assays inhibits YAC-1 lysis by NK-enriched populations from murine spleen. This is the first report that antagonism of PGE binding affects NK activity. Our studies demonstrate that these effects are mediated through inhibition of target-effector cell conjugate formation. Studies in which effector and target cells were pretreated separately indicate that the PGE-mediated effects are expressed at the target cell level.
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