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*
Research Center Borstel, Center for Medicine and Biosciences, Department of Immunochemistry and Biochemical Microbiology, Borstel, Germany;
Martin-Luther-Universität Halle-Wittenberg, Kardiologische Intensivmedizin, Forschungslabor, Halle (Saale), Germany;
XOMA Corporation, Berkeley, CA 94710;
§
European Molecular Biology Laboratory c/o DESY, Hamburg, Germany; and
¶
Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan
The activation of cells by endotoxin (LPS) is one of the early host responses to infections with Gram-negative bacteria. The lipid A part of LPS molecules is known to represent the endotoxic principle; however, the specific requirements for the expression of biologic activity are still not fully understood. We previously found that a specific molecular conformation (endotoxic conformation) is a prerequisite for lipid A to be biologically active. In this study, we have investigated the interdependence of molecular charge and conformation of natural and chemically modified LPS and lipid A and its transport and intercalation into phospholipid membranes mediated by human LPS-binding protein, as well as IL-6 production after stimulation of whole blood or PBMCs. We found that the number, nature, and location of negative charges strongly modulate the molecular conformation of endotoxin. In addition, the LPS-binding protein-mediated transport of LPS into phospholipid membranes depends on the presence of net negative charge, yet charge is only a necessary, but not a sufficient, prerequisite for transport and intercalation. The biologic activity is determined mainly by the molecular conformation: only conical molecules are highly biologically active, whereas cylindrical ones are largely inactive. We could demonstrate that the net negative charge of the lipid A component and its distribution within the hydrophilic headgroup strongly influence the molecular conformation and, therefore, also the biologic activity.
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