Endotoxin and GM-CSF-mediated down-regulation of macrophage apo E secretion is inhibited by a TNF-specific monoclonal antibody.
Macrophage activation is associated with increased secretion of monokines, proteases, arachidonic acid metabolites, reactive oxygen, and nitrogen intermediates and yet decreased secretion of apolipoprotein E (apo E). Although the kinetics of apo E down-regulation have been investigated, the mechanism(s) involved remains unknown. In the present study, the question of whether macrophage-activating factors such as lipopolysaccharide (LPS) and granulocyte-macrophage colony-stimulating factor (GM-CSF) directly result in apo E down-regulation or indirectly by inducing the secretion of other inflammatory mediators has been investigated. LPS-stimulated macrophages demonstrated a dose-dependent reduction in apo E secretion with a 70% decrease occurring following a 48-h incubation with 20 ng/ml LPS. Coculture of these cells with a neutralizing concentration of a hamster monoclonal antibody against murine tumor necrosis factor (TNF) inhibited the LPS-mediated reduction in apo E secretion. This inhibitory effect resulting from TNF neutralization was not observed using pooled hamster immunoglobulin G, or hamster monoclonals against murine interleukin-1 alpha (IL-1 alpha), IL-1 beta, or interferon-gamma. Similar results were observed when GM-CSF was used to induce apo E down-regulation. The inhibitory effects of TNF neutralization on endotoxin-induced apo E down-regulation were dependent on LPS concentration and were no longer apparent at concentrations greater than 200 ng/ml. These results suggest that an autocrine, TNF-dependent mechanism may play a role in the down-regulation of apo E secretion during macrophage activation.
Zuckerman
S H
SH
Lilly Research Labs, Indianapolis, Indiana 46285.
O'Neal
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000096:biosynthesis* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae / Q000276:immunology; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007700:Kinetics; D007739:L Cells; D008070:Lipopolysaccharides / Q000633:toxicity*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D004731:Endotoxins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor