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J. Biol. Chem., Vol. 283, Issue 27, 18702-18710, July 4, 2008

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Effect of Plasma Phospholipid Transfer Protein Deficiency on Lethal Endotoxemia in Mice^*

Thomas Gautier¹, Alexis Klein¹², Valérie Deckert, Catherine Desrumaux, Nicolas Ogier, Anne-Laure Sberna, Catherine Paul, Naig Le Guern, Anne Athias, Thomas Montange, Serge Monier, Françoise Piard, Xian-Cheng Jiang^¶, David Masson, and Laurent Lagrost³

From the INSERM, Centre de Recherche-UMR866, Faculté de Médecine, Institut Fédératif de Recherche Santé-STIC, Universitéde Bourgogne, 21079 Dijon, France, Centre Hospitalier Universitaire Dijon, Hôpital du Bocage, 21034 Dijon, France, and ^¶Department of Anatomy and Cell Biology, SUNY Downstate Medical Center, New York 11203

Lipopolysaccharides (LPS) are components of Gram-negative bacteria. The cellular response from the host to LPS is mediated through stepwise interactions involving the lipopolysaccharide-binding protein (LBP), CD14, and MD-2, which produces the rearrangement of TLR4. In addition to LBP, the lipid transfer/lipopolysaccharide-binding protein gene family includes the phospholipid transfer protein (PLTP). Here we show that the intravascular redistribution of LPS from the plasma lipoprotein-free fraction toward circulating lipoproteins is delayed in PLTP-deficient mice. In agreement with earlier in vitro studies, which predicted the neutralization of the endotoxic properties of LPS when associated with lipoproteins, significant increases in the plasma concentration of proinflammatory cytokines were found in PLTP-deficient as compared with wild type mice. Similar inflammatory damage occurred in tissues from wild type and PLTP-deficient mice 24 h after one single intraperitoneal injection of LPS but with a more severe accumulation of red blood cells in glomeruli of LPS-injected PLTP-deficient mice. Complementary ex vivo experiments on isolated splenocytes from wild type and PLTP-deficient mice further supported the ability of cell-derived PLTP to prevent LPS-mediated inflammation and cytotoxicity when combined with lipoprotein acceptors. Finally, PLTP deficiency in mice led to a significant increase in LPS-induced mortality. It is concluded that increasing circulating levels of PLTP may constitute a new and promising strategy in preventing endotoxic shock.

Received for publication, April 11, 2008

^* This work was supported by grants from the Université de Bourgogne, the Centre Hospitalier Universitaire de Dijon, the Conseil Régional de Bourgogne, INSERM, the Agence Nationale de la Recherche, and the Fondation de France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Recipient of a fellowship from the Ministère de l'Education Nationale, de la Recherche, et des Technologies.

³ To whom correspondence should be addressed: INSERM UMR866, Faculté de Médecine, 7 Boulevard Jeanne d'Arc, BP 87900, 21079 Dijon Cedex, France. Fax: 33-3-80-39-34-47; E-mail: laurent.lagrost{at}u-bourgogne.fr.

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