1. R-form LPS, the master key to the activation ofTLR4/MD-2-positive cells.
- Author
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Huber M, Kalis C, Keck S, Jiang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S, Beutler B, Galanos C, and Freudenberg MA
- Subjects
- Animals, Cells, Cultured, Escherichia coli genetics, Gram-Negative Bacterial Infections genetics, Gram-Negative Bacterial Infections immunology, Immunity, Innate drug effects, Immunity, Innate genetics, Lipopolysaccharide Receptors immunology, Lipopolysaccharides pharmacology, Lymphocyte Antigen 96 deficiency, Mice, Mice, Knockout, Salmonella genetics, Species Specificity, Toll-Like Receptor 4 deficiency, Escherichia coli immunology, Immunity, Innate immunology, Lipopolysaccharides immunology, Lymphocyte Antigen 96 immunology, Salmonella immunology, Toll-Like Receptor 4 immunology
- Abstract
Lipopolysaccharide (endotoxin, LPS) is a major recognition marker for the detection of gram-negative bacteria by the host and a powerful initiator of the inflammatory response to infection. Using S- and R-form LPS from wild-type and R-mutants of Salmonella and E. coli, we show that R-form LPS readily activates mouse cells expressing the signaling receptor Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD-2), while the S-form requires further the help of the LPS-binding proteins CD14 and LBP, which limits its activating capacity. Therefore, the R-form LPS under physiological conditions recruits a larger spectrum of cells in endotoxic reactions than S-form LPS. We also show that soluble CD14 at high concentrations enables CD14-negative cells to respond to S-form LPS. The presented in vitro data are corroborated by an in vivo study measuring TNF-alpha levels in response to injection of R- and S-form LPS in mice. Since the R-form LPS constitutes ubiquitously part of the total LPS present in all wild-type bacteria its contribution to the innate immune response and pathophysiology of infection is much higher than anticipated during the last half century. more...
- Published
- 2006
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