Lipopolysaccharide (LPS), an outer-membrane component of Gram-negative bacteria, interacts with LPS-binding protein and CD14, which present LPS to toll-like receptor 4 (refs 1, 2), which activates inflammatory gene expression through nuclear factor κB (NFκB) and mitogen-activated protein-kinase signalling3,4. Antibacterial defence involves activation of neutrophils that generate reactive oxygen species capable of killing bacteria5; therefore host lipid peroxidation occurs, initiated by enzymes such as NADPH oxidase and myeloperoxidase6. Oxidized phospholipids are pro-inflammatory agonists promoting chronic inflammation in atherosclerosis7; however, recent data suggest that they can inhibit expression of inflammatory adhesion molecules8. Here we show that oxidized phospholipids inhibit LPS-induced but not tumour-necrosis factor-α-induced or interleukin-1β-induced NFκB-mediated upregulation of inflammatory genes, by blocking the interaction of LPS with LPS-binding protein and CD14. Moreover, in LPS-injected mice, oxidized phospholipids inhibited inflammation and protected mice from lethal endotoxin shock. Thus, in severe Gram-negative bacterial infection, endogenously formed oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Furthermore, identified chemical structures capable of inhibiting the effects of endotoxins such as LPS could be used for the development of new drugs for treatment of sepsis.
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Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135–145 (2001)
Aderem, A. & Ulevitch, R. J. Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787 (2000)
Chow, J. C., Young, D. W., Golenbock, D. T., Christ, W. J. & Gusovsky, F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J. Biol. Chem. 274, 10689–10692 (1999)
Beutler, B. Tlr4: central component of the sole mammalian LPS sensor. Curr. Opin. Immunol. 12, 20–26 (2000)
Hampton, M. B., Kettle, A. J. & Winterbourn, C. C. Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. Blood 92, 3007–3017 (1998)
Zhang, R., Shen, Z., Nauseef, W. M. & Hazen, S. L. Defects in leukocyte-mediated initiation of lipid peroxidation in plasma as studied in myeloperoxidase-deficient subjects: systematic identification of multiple endogenous diffusible substrates for myeloperoxidase in plasma. Blood 99, 1802–1810 (2002)
Lusis, A. J. Atherosclerosis. Nature 407, 233–241 (2000)
Leitinger, N. et al. Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils. Proc. Natl Acad. Sci. USA 96, 12010–12015 (1999)
Watson, A. D. et al. Structurally identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo. J. Biol. Chem. 272, 13597–13607 (1997)
Bochkov, V. N. et al. Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca++/NFAT. Blood 99, 199–206 (2002)
Elass-Rochard, E. et al. Lactoferrin inhibits the endotoxin interaction with CD14 by competition with the lipopolysaccharide-binding protein. Infect. Immun. 66, 486–491 (1998)
Emancipator, K., Csako, G. & Elin, R. J. In vitro inactivation of bacterial endotoxin by human lipoproteins and apolipoproteins. Infect. Immun. 60, 596–601 (1992)
Kitchens, R. L., Thompson, P. A., Viriyakosol, S., O'Keefe, G. E. & Munford, R. S. Plasma CD14 decreases monocyte responses to LPS by transferring cell-bound LPS to plasma lipoproteins. J. Clin. Invest. 108, 485–493 (2001)
Wurfel, M. M. & Wright, S. D. Lipopolysaccharide-binding protein and soluble CD14 transfer lipopolysaccharide to phospholipid bilayers: preferential interaction with particular classes of lipid. J. Immunol. 158, 3925–3934 (1997)
Rustici, A. et al. Molecular mapping and detoxification of the lipid A binding site by synthetic peptides. Science 259, 361–365 (1993)
Christ, W. J. et al. E5531, a pure endotoxin antagonist of high potency. Science 268, 80–83 (1995)
Golenbock, D. T., Hampton, R. Y., Qureshi, N., Takayama, K. & Raetz, C. R. Lipid A-like molecules that antagonize the effects of endotoxins on human monocytes. J. Biol. Chem. 266, 19490–19498 (1991)
Tanamoto, K. & Azumi, S. Salmonella-type heptaacylated lipid A is inactive and acts as an antagonist of lipopolysaccharide action on human line cells. J. Immunol. 164, 3149–3156 (2000)
Frey, E. A. et al. Soluble CD14 participates in the response of cells to lipopolysaccharide. J. Exp. Med. 176, 1665–1671 (1992)
Su, G. L., Simmons, R. L. & Wang, S. C. Lipopolysaccharide binding protein participation in cellular activation by LPS. Crit Rev. Immunol. 15, 201–214 (1995)
Sugiyama, T. & Wright, S. D. Soluble CD14 mediates efflux of phospholipids from cells. J. Immunol. 166, 826–831 (2001)
Yu, B., Hailman, E. & Wright, S. D. Lipopolysaccharide binding protein and soluble CD14 catalyze exchange of phospholipids. J. Clin. Invest. 99, 315–324 (1997)
Lawrence, T., Gilroy, D. W., Colville-Nash, P. R. & Willoughby, D. A. Possible new role for NF-κB in the resolution of inflammation. Nature Med. 7, 1291–1297 (2001)
Cunningham, M. D. et al. Helicobacter pylori and Porphyromonas gingivalis lipopolysaccharides are poorly transferred to recombinant soluble CD14. Infect. Immun. 64, 3601–3608 (1996)
Scott, M. G., Vreugdenhil, A. C., Buurman, W. A., Hancock, R. E. & Gold, M. R. Cutting edge: cationic antimicrobial peptides block the binding of lipopolysaccharide (LPS) to LPS binding protein. J. Immunol. 164, 549–553 (2000)
Bradley, P. P., Priebat, D. A., Christensen, R. D. & Rothstein, G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J. Invest Dermatol. 78, 206–209 (1982)
This project was funded by the Austrian Science Foundation and by the ICP Program of the Austrian Federal Ministry for Education, Science and Culture.
The authors declare that they have no competing financial interests.
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Bochkov, V., Kadl, A., Huber, J. et al. Protective role of phospholipid oxidation products in endotoxin-induced tissue damage. Nature 419, 77–81 (2002) doi:10.1038/nature01023
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