PRODUCTION OF TUMOR-NECROSIS-FACTOR INDUCED BY SYNTHETIC LOW-TOXICITYLIPID-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 pre sent study, we investigated the mechanism by which DT-5461a induces TN F production in murine macrophage RAW 264 cells. DT-5461a mimicked the ability of LPS to induce TNF production in a dose-dependent manner. D T-5461a at higher concentrations inhibited specific binding of [H-3]LP S to the cells and reduced LPS-induced TNF production to the level ind uced by DT-5461a alone. In addition, DT-5461a, as well as LPS, induced tyrosine phosphorylation of MAP kinases, the early signal transductio n pathway of this production. Herbimycin A, an inhibitor of tyrosine k inase, inhibited the LPS- and DT-5461a-induced tyrosine phosphorylatio n, expression of TNF mRNA, and subsequent TNF secretion. These results suggest that DT-5461a and LPS induce TNF production in murine macroph ages through the common receptor sites and the similar early signaling pathway. (C) 1995 Academic Press, Inc.