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Brief Definitive Reports

Mark M. Wurfel^*, Brian G. Monks^,, Robin R. Ingalls^,, Russell L. Dedrick^||, Russell Delude^,, Dahua Zhou^*, Norbert Lamping^**, Ralf R. Schumann^**, Rolf Thieringer^¶, Matthew J. Fenton, Samuel D. Wright^*,¶, and Douglas Golenbock^,

From ^* The Rockefeller University, New York 10021; The Maxwell Finland Laboratory for Infectious Diseases, Boston, Massachusetts 02118; Boston University School of Medicine, Boston, Massachusetts 02118; ^|| XOMA Corporation, Berkeley, California 94710; ^¶ Merck Research Laboratories, Rahway, New Jersey 07065; ^** University Medical Center Charité, Humboldt-University, D-10117 Berlin, Germany

Gram-negative bacterial lipopolysaccharide (LPS) stimulates phagocytic leukocytes by interacting with the cell surface protein CD14. Cellular responses to LPS are markedly potentiated by the LPS-binding protein (LBP), a lipid-transfer protein that binds LPS aggregates and transfers LPS monomers to CD14. LBP also transfers LPS to lipoproteins, thereby promoting the neutralization of LPS. LBP present in normal plasma has been shown to enhance the LPS responsiveness of cells in vitro. The role of LBP in promoting LPS responsiveness in vivo was tested in LBP-deficient mice produced by gene targeting in embryonic stem cells. Whole blood from LBP-deficient animals was 1,000-fold less responsive to LPS as assessed by the release of tumor necrosis factor (TNF)-. Blood from gene-targeted mice was devoid of immunoreactive LBP, essentially incapable of transferring LPS to CD14 in vitro, and failed to support cellular responses to LPS. These activities were restored by the addition of exogenous recombinant murine LBP to the plasma. Despite these striking in vitro findings, no significant differences in TNF- levels were observed in plasma from wild-type and LBP-deficient mice injected with LPS. These data suggest the presence of an LBP-independent mechanism for responding to LPS. These LBP knockout mice may provide a tool for discovering the nature of the presumed second mechanism for transferring LPS to responsive cells.

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