We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Endotoxin·albumin complexes transfer endotoxin monomers to MD-2 resulting in activation of TLR4.
- Authors
Esparza, Gregory A; Teghanemt, Athmane; Zhang, DeSheng; Gioannini, Theresa L; Weiss, Jerrold P
- Abstract
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 (Eagg, Mr ≥ 20 million) in PBS with ≥ 0.1% albumin in the absence of divalent cations Ca2+ and Mg2+, yields E·albumin complexes (Mr ∼70,000). E·albumin transfers E monomers to sMD-2 or sMD-2·TLR4 ectodomain (TLR4ecd) with a ‘Kd’ of ∼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.
- Subjects
ENDOTOXINS; ALBUMINS; MONOMERS; GRAM-negative bacteria; CARRIER proteins; IMMUNOLOGY; TOLL-like receptors; MOLECULAR recognition
- Publication
Innate Immunity, 2012, Vol 18, Issue 3, p478
- ISSN
1753-4259
- Publication type
Article
- DOI
10.1177/1753425911422723