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Monomeric endotoxin:protein complexes are essential for TLR4-dependent cell activation

Department of Internal Medicine, University of Iowa and the Veterans' Administration Medical Center, Iowa City, Iowa, USA, Department of Biochemistry, University of Iowa and the Veterans' Administration Medical Center, Iowa City, Iowa, USA, theresa-gioannini{at}uiowa.edu

A. Teghanemt

Department of Internal Medicine, University of Iowa and the Veterans' Administration Medical Center, Iowa City, Iowa, USA

DeS. Zhang

Department of Internal Medicine, University of Iowa and the Veterans' Administration Medical Center, Iowa City, Iowa, USA

E.N. Levis

Department of Internal Medicine, University of Iowa and the Veterans' Administration Medical Center, Iowa City, Iowa, USA

J.P. Weiss

Department of Internal Medicine, University of Iowa and the Veterans' Administration Medical Center, Iowa City, Iowa, USA, Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa and the Veterans' Administration Medical Center, Iowa City, Iowa, USA

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:CD14 is 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.

Key Words: CD14 • Gram-negative bacteria • lipopolysaccharide • Toll-like receptors • MD-2 • lipopolysaccharide binding protein

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