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Papers In Press, published online ahead of print April 19, 2004
Immunochemistry and Biochemical Microbiology, Research Center Borstel, Borstel D-23845
Corresponding Author: useydel{at}fz-borstel.de
For the elucidation of the very early steps of immune cell activation by endotoxins (lipopolysaccharide, LPS1) leading to the production and release of proinflammatory cytokines the question concerning the biologically active unit of endotoxins has to be addressed: Are monomeric endotoxin molecules able to activate cells or is the active unit represented by larger endotoxin aggregates? This question has been answered controversely in the past. Inspired by the observation that natural isolates of lipid A, the lipid moiety of LPS harboring its endotoxic principle, from Escherichia coli express a higher endotoxic activity than same amounts of the synthetic E.coli-like hexaacylated lipid A (compound 506), we looked closer at the chemical composition of natural isolates. We found in these isolates that the largest fraction was hexaacylated, but also significant amounts of penta- and tetraacylated molecules were present which, administered to human mononuclear cells, may antagonize the induction of cytokines by biologically active hexaacylated endotoxins. We prepared separate aggregates of either compound 506 or 406 (tetraacylated precursor IVa) and mixed these at different molar ratios as well as mixed aggregates containing both compounds in the same ratios. Surprisingly, the latter mixtures showed higher endotoxic activity than that of the pure compound 506 up to an admixture of 20% of compound 406. Similar results were obtained when using various phospholipids instead of compound 406. These observations can only be understood by assuming that the active unit of endotoxins is the aggregate. We further confirmed this result by preparing monomeric lipid A and LPS by a dialysis procedure and found that – at same concentrations – only aggregates were biologically active, whereas the monomers showed no activity.
J. Biol. Chem, 10.1074/jbc.M401231200
Submitted on February 4, 2004
Revised on April 19, 2004
Accepted on April 19, 2004
Aggregates are the biologically active units of endotoxin
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