Suppression of macrophage oxidative metabolism by products of malignant and nonmalignant cells.

Abstract

Each of 11 tumors tested produced a factor that markedly suppressed the ability of macrophages to release H2O2 or O.2- in response to phorbol myristate acetate or zymosan. Four of seven normal cell types produced a similar activity, which was 3.5-7 times lower in titer than that in tumor cell-conditioned medium (TCM), and which was much more rapidly reversible in its effects. TCM caused 50% inhibition of H2O2 release when it was present in the medium for 48 h at a concentration of 13%, or when 100% TCM was present in the medium for 18 h. The H2O2-releasing capacity of macrophages incubated in TCM only returned to control levels by 6 d after its removal. TCM prevented augmentation of H2O2-releasing capacity by lymphokines. The titer of suppressive activity in TCM depended on both the concentration of tumor cells and the duration of their incubation. TCM did not augment the activity of catalase, myeloperoxidase, glutathione peroxidase, or glutathione reductase or the content of glutathione within macrophages, suggesting that decreased synthesis rather than increased catabolism was responsible for reduced secretion of H2O2. Suppression of the release of H2O2 or O.2- by TCM appeared to be a relatively specific effect, in that TCM increased macrophage spreading and adherence to glass while exerting little influence on rates of phagocytosis, synthesis of protein, or secretion of lysozyme, plasminogen activator, or arachidonic acid and its metabolites. Thus, tumor cells and some normal cells can secrete a factor that selectively deactivates macrophage oxidative metabolism.