Acute-phase concentrations of lipopolysaccharide (LPS)-binding protein inhibit innate immune cell activation by different LPS chemotypes via different mechanisms.
The chain length of bacterial lipopolysaccharide (LPS) is a crucial factor for host-pathogen interaction during bacterial infection. While rough (R)-type and smooth (S)-type LPSs have been shown to differ in their ability to interact with the bactericidal/permeability-increasing protein, little is known about the differential mode of interaction with the acute-phase reactant LPS-binding protein (LBP). At lower concentrations, LBP catalyzes the binding of LPS to CD14 and enhances LPS-induced cellular activation via Toll-like receptor 4. In humans, however, concentrations of LBP in serum increase during an acute-phase response, and these LBP concentrations exhibit inhibitory effects in terms of cellular activation. The mechanisms of inhibition of LPS effects by LBP are not completely understood. Here, we report that human high-dose LBP (hd-LBP) suppresses binding of both R-type and S-type LPS to CD14 and inhibits LPS-induced nuclear translocation of NF-kappaB, although cellular uptake of R-type LPS was found to be increased by hd-LBP. In contrast, we found that hd-LBP enhanced the binding and uptake of S-type LPS only under serum-free conditions, whereas in the presence of serum, hd-LBP inhibited cellular binding and uptake. This inhibitory effect of serum could be mimicked by the addition of purified high-density lipoprotein (HDL) to serum-free medium, indicating an LBP-mediated transfer of preferentially S-type LPS to plasma lipoproteins such as HDL. A complete understanding of the host's mechanisms to modulate the proinflammatory effects of LPS will most likely help in the understanding of inflammation and infection and may lead to novel therapeutic intervention strategies.
Hamann
Lutz
L
Institute for Microbiology and Hygiene, Charité University Medical Center, Humboldt University Berlin, Dorotheenstrasse 96, 10117 Berlin, Germany. lutz.hamann@charite.de
Alexander
Christian
C
Stamme
Cordula
C
Zähringer
Ulrich
U
Schumann
Ralf R
RR
D000209:Acute-Phase Proteins / Q000502:physiology*; D000210:Acute-Phase Reaction / Q000097:blood; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000502:physiology*; D006224:Cricetinae; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology*; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008075:Lipoproteins, HDL; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein