ABSTRACT
Human peripheral blood monocytes were cultured and exposed to plant diterpenes, indole alkaloids and polyacetates with various degrees of tumor-promoting activity. The effect of the above-mentioned encounter on monocyte function was examined, as expressed by H2O2 production and lysis of dog erythrocytes by the cells, and the inhibition of 3H-PDBu binding to the monocytes by the various test agents. The most effective reagents in both activation of monocyte function and inhibition of 3H-PDBu binding were 12-0-tetradecanoyl-phorbol 13-acetate (TPA), phorbol 12, 13 dibutyrate, teleocidin, and aplysiatoxin which are known to be strong tumor promoters. Strong stimulation of monocyte function was also exerted by the weak tumor promoters, phorbol 12-retinoate 13-acetate, mezerein and debromoaplysiatoxin. Non-tumor-promoting phorbol diterpenes such as phorbol 12, 13-diacetate, phorbol 12-myristate, phorbol 13-acetate and 4-alpha TPA were 1,000 times less effective than TPA in monocyte stimulation and inhibition of 3H-PDBu binding. These results indicate that stimulation of human monocyte H2O2 production and related cytotoxicity might discriminate effectively between tumor-promoting and non-tumor-promoting reagents.
Subject(s)
Caenorhabditis elegans Proteins , Carcinogens/pharmacology , Diterpenes/pharmacology , Lyngbya Toxins/pharmacology , Monocytes/drug effects , Phorbol Esters/pharmacology , Protein Kinase C , Receptors, Drug , Binding, Competitive , Carrier Proteins , Cells, Cultured , Cytotoxicity, Immunologic/drug effects , Hemolysis/drug effects , Humans , Hydrogen Peroxide/metabolism , Oxygen Consumption/drug effects , Receptors, Immunologic/metabolism , Structure-Activity RelationshipABSTRACT
Red blood cells (RBCs) from various animals, when exposed to oxidative burst (OB)-stimulated mouse macrophages, showed differences in sensitivity to OB dependent lysis. The increasing order of sensitivity was: mouse, hamster, rabbit, guinea pig, sheep and human RBCs. The degree of OB dependent hemolysis did not correlate with either the capacity of the various cells to degrade H2O2 or their osmotic fragility. The relative sensitivity of the various RBCs to OB products generated by macrophages concurred with their sensitivity to H2O2 generated by an enzymatic system. The differential sensitivity may be correlated with the sphingomyelin content of the cells.
Subject(s)
Cytotoxicity, Immunologic , Erythrocytes/physiology , Hemolysis , Macrophages/metabolism , Animals , Blood Glucose/metabolism , Cells, Cultured , Chromium Radioisotopes , Erythrocytes/enzymology , Glucose Oxidase/metabolism , Guinea Pigs , Humans , Hydrogen Peroxide/blood , In Vitro Techniques , Macrophages/immunology , Mice , Mice, Inbred C57BL , Osmotic Fragility , Oxidation-Reduction , Rabbits , SheepABSTRACT
Mouse peritoneal macrophages elicit an oxidative burst (OB) response upon stimulation with the tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate (TPA). In this study we compare the OB-stimulating capacity of phorbol ester derivatives, structurally related to TPA, which differ in their tumor-promoting activity. Non-tumor-promoting derivatives such as phorbol 13-acetate, phorbol 12-myristate, TPA-20-aldehyde and 4-O-methyl TPA were tested. These reagents stimulate macrophages to generate OB products such as O-2 and H2O2, yet the amounts required for stimulation are 1,000 times higher than the amounts of TPA required to elicit a comparable response. It has also been observed that, in the same order of magnitude, the above-mentioned derivatives are less efficient than TPA in rendering macrophages cytolytic toward erythrocytes. Another strong tumor promoter tested, teleocidin, has been found to be as potent as TPA in the activation of macrophage OB and in related activities.
