Production of tumor necrosis factor induced by synthetic low-toxicity lipid a analog, DT-5461a, is mediated by LPS receptor sites and tyrosine kinase—MAP kinase signaling pathway in murine macrophages

The synthetic low-toxicity lipid A analog DT-5461a induces endogenous TNF production in mice. The activity of TNF so induced is probably the main contributor to the antitumor effect of this compound. In the present study, we investigated the mechanism by which DT-5461a induces TNF production in muri...

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Bibliographic Details
Published in:Cellular immunology 1995, Vol.160 (1), p.1-7
Main Authors: Joto, Noriko, Akimoto, Toshihiko, Someya, Kazuhiko, Tohgo, Akiko
Format: Article
Language:English
Subjects:
Animals
Benzoquinones
Binding, Competitive
Blotting, Western
Cell Line, Transformed
Disaccharides - pharmacology
Lactams, Macrocyclic
Lipid A - analogs & derivatives
Lipid A - pharmacology
Lipopolysaccharide Receptors
Lipopolysaccharides - metabolism
Lipopolysaccharides - pharmacology
Macrophages - immunology
Mice
Protein Kinases - physiology
Protein-Tyrosine Kinases - physiology
Quinones - pharmacology
Receptors, Immunologic - physiology
Rifabutin - analogs & derivatives
RNA, Messenger - biosynthesis
RNA, Messenger - drug effects
Signal Transduction - immunology
Tumor Necrosis Factor-alpha - biosynthesis
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Summary:The synthetic low-toxicity lipid A analog DT-5461a induces endogenous TNF production in mice. The activity of TNF so induced is probably the main contributor to the antitumor effect of this compound. In the present study, we investigated the mechanism by which DT-5461a induces TNF production in murine macrophage RAW 264 cells. DT-5461a mimicked the ability of LPS to induce TNF production in a dose-dependent manner. DT-5461a at higher concentrations inhibited specific binding of [ 3H]LPS to the cells and reduced LPS-induced TNF production to the level induced by DT-5461a alone. In addition, DT-5461a, as well as LPS, induced tyrosine phosphorylation of MAP kinases, the early signal transduction pathway of this production. Herbimycin A, an inhibitor of tyrosine kinase, inhibited the LPS- and DT-5461a-induced tyrosine phosphorylation, expression of TNF mRNA, and subsequent TNF secretion. These results suggest that DT-5461a and LPS induce TNF production in murine macrophages through the common receptor sites and the similar early signaling pathway.
ISSN:0008-8749
1090-2163
DOI:10.1016/0008-8749(95)80002-Z