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Native High-Density Lipoprotein Augments Monocyte Responses to Lipopolysaccharide (LPS) by Suppressing the Inhibitory Activity of LPS-Binding Protein¹

Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75390

High-density lipoprotein (HDL) is an abundant plasma lipoprotein that is generally thought to be anti-inflammatory in both health and infectious disease. It binds and neutralizes the bioactivity of the potent bacterial lipids, LPS and lipoteichoic acid, that stimulate host innate immune responses. LPS-binding protein (LBP) plays an important role in augmenting leukocyte responses to LPS, whereas high concentrations of LBP, in the range of those found in plasma, can be inhibitory. We found that native HDL (nHDL) augmented human monocyte responses to LPS in the presence of inhibitory concentrations of LBP as measured by production of TNF and other cytokines. HDL did not stimulate cells in the absence of LPS, and it did not augment responses that were stimulated by IL-1 or lipoteichoic acid. This activity of HDL was inhibited by trypsin treatment, suggesting that one or more protein constituents of HDL are required. In contrast to nHDL, low-density lipoprotein, and reconstituted HDL did not possess this activity. The total lipoprotein fraction of normal plasma had activity that was similar to that of nHDL, whereas lipoproteins from septic patients with reduced HDL levels had a reduced ability to augment responses to LPS; this activity was restored by adding normal HDL to the patient lipoproteins. Our results demonstrate a novel proinflammatory activity of HDL that may help maintain sensitive host responses to LPS by suppressing the inhibitory activity of LBP. Our findings also raise the possibility that the decline of HDL during sepsis may help control the response to LPS.

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 This work was supported by National Institutes of Health Grant AI45896 from the National Institute of Allergy and Infectious Diseases.

² Address correspondence and reprint requests to Dr. Richard L. Kitchens, Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9113. E-mail address: richard.kitchens{at}UTSouthwestern.edu

³ Abbreviations used in this paper: LBP, LPS-binding protein; HDL, high-density lipoprotein; LTA, lipoteichoic acid; nHDL, native HDL; sCD14, soluble CD14; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein; R-HDL, reconstituted HDL; apo, apolipoprotein; SAA, serum amyloid A; HDL-C, HDL cholesterol; HDL-PL, HDL-phospholipid; VD₃, 1,25 dihydroxyvitamin D₃.