Journal article
Evidence of a Specific Interaction between New Synthetic Antisepsis Agents and CD14
Biochemistry (Easton), Vol.48(51), pp.12337-12344
12/29/2009
DOI: 10.1021/bi901601b
PMCID: PMC2802518
PMID: 19928913
Abstract
Synthetic molecules derived from natural sugars with a positively charged amino group or ammonium salt and two lipophilic chains have been shown to inhibit TLR4 activation In vitro and in vivo. To characterize the mechanism of action of this class of molecules, we investigated possible interactions with the extracellular components that bind and shuttle endotoxin [lipopolysaccharide (LPS)] to TLR4, namely, LBP, CD 14, and MD-2. Molecules that inhibited TLR4 activation inhibited LBP center dot CD14-dependent transfer of endotoxin monomers derived from aggregates of tritiated lipooligosaccharide ([H-3]LOS) from Neisseria meninigitidis to MD-2-TLR4, resulting in a reduced level of formation of a ([H-3]LOS center dot MD-2 center dot TLR4(ECD))(2) (Mr similar to 190000) complex. This effect Was due to inhibition of the transfer of [3 H]LOS from aggregates in solution to sCD14 with little or no effect on [H-3]LOS shuttling from [H-3]LOS center dot sCD14 to MD-2. These compounds also inhibited transfer of the [H-3]LOS monomer from full-length CD14 to a truncated, polyhistidine-tagged CD14. Dose-dependent inhibition of the transfer of [H-3]LOS between the two forms of CD 14 was observed with each of three different synthetic compounds that inhibited TLR4 activation but not by another structurally related analogue that lacked TLR4 antagonistic activity. Saturation transfer difference (STD) NMR data showed direct binding to CD14 by the synthetic TLR4 antagonist mediated principally through the lipid chains of the synthetic compound. Taken together, Our findings strongly suggest that these compounds inhibit TLR4 activation by endotoxin by competitively Occupying CD14 and thereby reducing the level of delivery of activating endotoxin to MD-2 center dot TLR4.
Details
- Title: Subtitle
- Evidence of a Specific Interaction between New Synthetic Antisepsis Agents and CD14
- Creators
- Matteo Piazza - University of Milano-BicoccaLiping Yu - University of IowaAthmane Teghanemt - University of IowaTheresa Gioannini - University of IowaJerrold Weiss - Univ Iowa, Dept Microbiol, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52246 USAFrancesco Peri - University of Milano-Bicocca
- Resource Type
- Journal article
- Publication Details
- Biochemistry (Easton), Vol.48(51), pp.12337-12344
- DOI
- 10.1021/bi901601b
- PMID
- 19928913
- PMCID
- PMC2802518
- NLM abbreviation
- Biochemistry
- ISSN
- 0006-2960
- eISSN
- 1520-4995
- Publisher
- Amer Chemical Soc
- Number of pages
- 8
- Grant note
- Veterans Administration; US Department of Veterans Affairs R01AI059372 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) AI05732 / National Institute of Allergy and Infectious Disease; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Language
- English
- Date published
- 12/29/2009
- Academic Unit
- Infectious Diseases; Biochemistry and Molecular Biology; Medicine Administration; Internal Medicine
- Record Identifier
- 9984632134802771
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