title: Monomeric endotoxin:protein complexes are essential for TLR4-dependent cell activation.
abstract: Potent TLR4-dependent cell activation by Gram-negative bacterial endotoxin depends on sequential endotoxin?protein and protein?protein interactions with LBP, CD14, MD-2 and TLR4. LBP and CD14 combine, in an albumin-dependent fashion, to extract single endotoxin molecules from purified endotoxin aggregates (E(agg)) or the bacterial outer membrane and form monomeric endotoxin:CD14 complexes that are the preferred presentation of endotoxin for transfer to MD-2. Endotoxin in endotoxin:CD14is readily transferred to MD-2, again in an albumin-dependent manner, to form monomeric endotoxin:MD-2 complex. This monomeric endotoxin:protein complex (endotoxin:MD-2) activates TLR4 at picomolar concentrations, independently of albumin, and is, therefore, the apparent ligand in endotoxin-dependent TLR4 activation. Tetra-, penta-, and hexa-acylated forms of meningococcal endotoxin (LOS) react similarly with LBP, CD14, and MD-2 to form endotoxin:MD-2 complexes. However, tetra- and penta-acylated LOS:MD-2 complexes are less potent TLR4 agonists than hexa-acylated LOS:MD-2. This is mirrored in the reduced activity of tetra-, penta- versus hexa-acylated LOS aggregates (LOS(agg)) + LBP toward cells containing mCD14, MD-2, and TLR4. Therefore, changes in agonist potency of under-acylated meninigococcal LOS are determined by differences in properties of monomeric endotoxin:MD-2.
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52241, USA. theresa-gioannini@uiowa.edu
authors.forename: T L
authors.initials: TL
authors.lastname: Gioannini
authors.forename: A
authors.initials: A
authors.lastname: Teghanemt
authors.forename: DeS
authors.initials: D
authors.lastname: Zhang
authors.forename: E N
authors.initials: EN
authors.lastname: Levis
authors.forename: J P
authors.initials: JP
authors.lastname: Weiss
mesh_terms: D002460:Cell Line; D002850:Chromatography, Gel; D004731:Endotoxins / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology*; D009345:Neisseria meningitidis / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D004731:Endotoxins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors