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Mechanism of Nonspecific Macrophage-Mediated Cytotoxicity: Evidence for Lack of Dependence upon Oxygen¹

Division of Hematology-Oncology, Department of Medicine, The Center for the Health Sciences, University of California, Los Angeles, California 90024

Abstract

Peritoneal macrophages elicited in C3H/HJ mice by the i.p. injection of Corynebacterium parvum were cytotoxic to allogeneic virus-transformed fibroblasts in vitro. Cytotoxicity was demonstrated in a morphologic (plaque) assay, and quantitated by measuring macrophage-mediated inhibition of incorporation of ³H-thymidine by the target cells. The cytotoxic effect was well established by 6 hr of macrophage-fibroblast interaction, and was retained in cultures from which the supernatant was removed before the addition of ³H-thymidine. Cytotoxic activity of macrophages diminished rapidly after 22 hr of cultivation in vitro. Maximal cytotoxic effect could be prolonged by addition of C. parvum, 50 µg/ml, to macrophage monolayers preincubated in vitro for 22 hr. It could neither be retained nor regenerated when C. parvum was added to monolayers greater than 22-hr old.

C. parvum-activated macrophages, grown under anaerobic conditions for 8 hr, retained the ability to phagocytize heat-killed Candida albicans and to exclude trypan blue dye. There was a small but significant reduction in the ability of macrophages to inhibit ³H-thymidine incorporation by target fibroblasts under anaerobic conditions.

The cytotoxic effect of activated macrophages in air was not altered by the presence of catalase and was enhanced by enzymatically active superoxide dismutase. We conclude that the processes involved in macrophage-mediated cytotoxicity against allogeneic fibroblasts in this system are largely independent of oxygen.

Footnotes

¹ This work was supported by United States Public Health Service Grants AI 12171, CA 15688, CA 15619, and a grant from the California Institute for Cancer Research.

² TCS is a recipient of a Fulbright-Hays Travel Award.

³ MJC is a recipient of a grant from the Bowyer Foundation.