SELECTIVE SENSITIVITY OF MACROPHAGES TO CYTOTOXICITY BY INHIBITORS OFMACROMOLECULAR-SYNTHESIS - INDUCTION OF APOPTOSIS

Initial studies designed to measure the effect of inhibiting RNA synth esis by dactinomycin on macrophage functions revealed that the cells w ere uniformly killed at concentrations that have been routinely used t o inhibit RNA synthesis in other cell types, We, thus, determined the dose curve for the cytotoxicity of dactinomycin for macrophages and tw o other cell types, L929 cells and splenic lymphocytes. Macrophages we re extremely sensitive to the cytotoxicity of dactinomycin compared to the other cell types. Submicromolar concentrations that induced 100% cytotoxicity in macrophages caused little death in L929 cells or lymph ocytes. Concentrations of dactinomycin that inhibited RNA synthesis by 40% in macrophages induced almost complete cell death but inhibition of over 80% of RNA synthesis in L929 cells or lymphocytes induced no m easurable cytotoxicity, Macrophages did take up more dactinomycin than other cells but the amount was not sufficient to account for the larg e differences in cytotoxicity, We next tested the effects of doxorubic in and cycloheximide and found that macrophages were also extremely se nsitive to killing by these compounds, and there was a very close asso ciation between the amount of inhibition of protein synthesis and the amount of toxicity, The morphology of macrophages exposed to these age nts was consistent with death by apoptosis, This was further supported by assays measuring membrane integrity and DNA fragmentation, These d ata demonstrate that inhibition of macromolecular synthesis in macroph ages, by different mechanisms, causes macrophages to undergo apoptosis , They further suggest that, in contrast to other cell types that requ ire protein synthesis for apoptosis, macrophages require the synthesis of certain proteins to avoid apoptosis.