LIPID-IVA INHIBITS SYNTHESIS AND RELEASE OF TUMOR-NECROSIS-FACTOR INDUCED BY LIPOPOLYSACCHARIDE IN HUMAN WHOLE-BLOOD EXVIVO

Tumor necrosis factor (TNF) released by lipopolysaccharide (LPS)-stimulated mononuclear phagocytes is a critical mediator of sepsis. We examined the capacities of rough mutant Salmonella typhimurium LPS (Rc) and LPS partial structures lipid A, monophosphoryl lipid A (MPLA), lipid IVA, and lipid X to induce production of TNF in whole blood. Rc LPS (0.0001-10 ng/ml) produced a dose-dependent release ofTNF as determined by cytotoxicity ofactinomycin D-sensitized L929 murine fibroblasts. Lipid A, MPLA, lipid IVe, and lipid X exhibited decreasing capacities to stimulate production of TNF in whole blood, respectively. Fractional dearylation of LPS by incubation with acyloxyacyl hydrolase isolated from human leukocytes produced a reduction in the capacity ofLPS to induce TNF release in whole blood. Maximal enzymatic dearylation reduced activity of LPS by >100-fold. Coincubation with lipid IVA inhibited TNF release induced by Rc LPS or lipid A, but not by phorbol ester. In contrast, MPLA, lipid X, and deacylated LPS failed to inhibit LPS-stimulated release of TNF. Corresponding to the inhibition of the release of TNF protein, lipid IVn also inhibited the accumulation of TNF mRNA in LPS-stimulated mononuclear cells. These results suggest that lipid IVY may act as a competitive antagonist of LPS, perhaps at the receptor level. © 1990, Rockefeller University Press., All rights reserved.