Effects of various inhibitors of arachidonic acid oxygenation on macrophage superoxide release and tumoricidal activity.
Macrophages release a variety of arachidonic acid metabolites after treatment with various membrane triggers or particulate stimuli. We examined the role of phospholipase and lipoxygenase inhibitors in the modulation of superoxide production and tumor cytolysis by murine macrophages. Superoxide was induced by the soluble stimulus, phorbol myristate acetate (PMA), and the particulate stimulus, opsonized zymosan, and was measured by the reduction of ferricytochrome c with the use of a micro ELISA reader. Macrophage-mediated tumor cytolysis was induced by hybridoma-derived, macrophage-activating factor (MAF) and was quantitated by 51Cr release from P815 target cells. In both assays, 72-hr peptone-elicited macrophages were used. Dexamethasone, and to a lesser degree hydrocortisone, inhibited superoxide release and MAF-induced tumor cytolysis. Inhibition in the superoxide assay required pretreatment with corticosteroid. Only the gold compound, auranofin, inhibited superoxide when given simultaneously with stimulant. Other phospholipase inhibitors, including mepacrine and 4-bromophenacyl bromide, and several lipoxygenase inhibitors, including BW755c, nordihydroguaiaretic acid (NDGA), and 5,8,11,14-eicosatetraynoic acid (ETYA), failed to modulate either macrophage response at nontoxic concentrations. At the concentrations tested in the tumoricidal and superoxide assays, mepacrine and 4-bromophenacyl bromide inhibited the release of 14C-arachidonic acid from macrophages stimulated with opsonized zymosan. Our data strongly suggest that corticosteroids suppress macrophage superoxide production and tumoricidal function by a nonphospholipase-dependent mechanism.
Schultz
R M
RM
Nanda
S K
SK
Altom
M G
MG
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001310:Auranofin; D006051:Aurothioglucose / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D016859:Lipoxygenase Inhibitors; D008222:Lymphokines / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D016215:Macrophage-Activating Factors; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental; D010587:Phagocytosis / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015054:Zymosan / Q000276:immunology
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D008222:Lymphokines; D016215:Macrophage-Activating Factors; D013481:Superoxides; D016718:Arachidonic Acid; D006051:Aurothioglucose; D001310:Auranofin; D015054:Zymosan; D013755:Tetradecanoylphorbol Acetate