Endotoxin suppresses the generation of O2- and H2O2 by "resting" and lymphokine-activated human blood-derived macrophages.
In evaluation of macrophage-activating principles other than lymphokines, we systematically investigated the effects of endotoxin on the formation of reactive oxygen intermediates measured by chemiluminescence. Surprisingly, endotoxin exposure of human blood monocytes cultured in vitro for 36 h lessened in a dose-dependent manner the amount of O2- and H2O2 secreted in response to phagocytosis of opsonized particles or to PMA, a soluble stimulant. Blunting of the respiratory burst by endotoxin was independent from the state of macrophage activation. Endotoxin thus impaired formation of reactive oxygen metabolites before, during, or after activation of macrophages by IFN-gamma. The median effective concentration (EC50) was 1.95 ng/ml LPS in resting macrophages and 7.22 ng/ml in IFN-gamma-activated macrophages with as little as 0.1 ng/ml reproducibly giving detectable inhibition. Lipid A, but not "detoxified" monophosphoryl lipid A gave an inhibition comparable to that of complete LPS. The inhibitory effect of endotoxin was attenuated by dexamethasone, but not by inhibitors of arachidonic acid metabolism. Because endotoxin induces and dexamethasone inhibits production of some monokines, it is tempting to speculate that endotoxin is part of an autoregulatory system of mononuclear phagocytes for the control of excessive production of potentially harmful oxidants. The two monokines identified to be secreted in response to LPS and to be inhibited by dexamethasone, IL-1 and TNF, had, however, no comparable effect on chemiluminescence.
Rellstab
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P
Department of Medicine, University of Zürich Medical School, Switzerland.
Schaffner
A
A
D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008222:Lymphokines / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D010101:Oxygen Consumption / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004731:Endotoxins; D008222:Lymphokines; D013481:Superoxides; D003907:Dexamethasone; D006861:Hydrogen Peroxide; D013755:Tetradecanoylphorbol Acetate