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Infection and Immunity, November 2001, p. 6942-6950, Vol. 69, No. 11
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.11.6942-6950.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Dual Role of Lipopolysaccharide (LPS)-Binding Protein in Neutralization of LPS and Enhancement of LPS-Induced Activation of Mononuclear Cells

Thomas Gutsmann,1 Mareike Müller,1 Stephen F. Carroll,2 Roger C. MacKenzie,3 Andre Wiese,1 and Ulrich Seydel1,*

Department of Immunochemistry and Biochemical Microbiology, Center for Medicine and Biosciences, Research Center Borstel, D-23845 Borstel, Germany1; XOMA (US) LLC, Berkeley, California 947102; and Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada K1A OR63

Received 26 April 2001/Returned for modification 2 August 2001/Accepted 20 August 2001

The lipopolysaccharide (LPS)-binding protein (LBP) has a concentration-dependent dual role in the pathogenesis of gram-negative sepsis: low concentrations of LBP enhance the LPS-induced activation of mononuclear cells (MNC), whereas the acute-phase rise in LBP concentrations inhibits LPS-induced cellular stimulation. In stimulation experiments, we have found that LBP mediates the LPS-induced cytokine release from MNC even under serum-free conditions. In biophysical experiments we demonstrated that LBP binds and intercalates into lipid membranes, amplified by negative charges of the latter, and that intercalated LBP can mediate the CD14-independent intercalation of LPS into membranes in a lipid-specific and temperature-dependent manner. In contrast, prior complexation of LBP and LPS inhibited binding of these complexes to membranes due to different binding of LBP to LPS or phospholipids. This results in a neutralization of LPS and, therefore, to a reduced production of tumor necrosis factor by MNC. We propose that LBP is not only present as a soluble protein in the serum but may also be incorporated as a transmembrane protein in the cytoplasmic membrane of MNC and that the interaction of LPS with membrane-associated LBP may be an important step in LBP-mediated activation of MNC, whereas LBP-LPS complexation in the serum leads to a neutralization of LPS.

* Corresponding author. Mailing address: Research Center Borstel, Center for Medicine and Biosciences, Department of Immunochemistry and Biochemical Microbiology, Parkallee 10, D-23845 Borstel, Germany. Phone: 49 (0) 4537 188-232. Fax: 49 (0) 4537 188-632. E-mail: useydel{at}fz-borstel.de.

Infection and Immunity, November 2001, p. 6942-6950, Vol. 69, No. 11
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.11.6942-6950.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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