Journal
INNATE IMMUNITY
Volume 18, Issue 3, Pages 478-491Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/1753425911422723
Keywords
Albumin; endotoxin; MD-2; Toll-like receptor 4; CD14
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Funding
- U.S. Public Health Service [A105732]
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development
- University of Iowa [T32 A10075]
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Response to Gram-negative bacteria (GNB) is partially mediated by the recognition of GNB-derived endotoxin by host cells. Potent host response to endotoxin depends on the sequential interaction of endotoxin with lipopolysaccharide binding protein (LBP), CD14, MD-2 and TLR4. While CD14 facilitates the efficient transfer of endotoxin monomers to MD-2 and MD-2.TLR4, activation of MD-2.TLR4 can occur in the absence of CD14 through an unknown mechanism. Here, we show that incubation of purified endotoxin (E) aggregates (E-agg, M-r >= 20 million) in PBS with >= 0.1% albumin in the absence of divalent cations Ca2+ and Mg2+, yields E.albumin complexes (M-r similar to 70,000). E.albumin transfers E monomers to sMD-2 or sMD-2.TLR4 ectodomain (TLR4(ecd)) with a 'K-d' of similar to 4 nM and induces MD-2.TLR4-dependent, CD14-independent cell activation with a potency only 10-fold less than that of monomeric E.CD14 complexes. Our findings demonstrate, for the first time, a mechanistic basis for delivery of endotoxin monomers to MD-2 and for activation of TLR4 that is independent of CD14.
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