Abstract 317: Synthetic HDL Inhibits Endotoxin-induced Inflammatory Cytokine Production in Macrophages Through Neutralization of Endotoxins and Suppression of TLR Signaling

Abstract

HDL plays critical roles in the regulation of inflammatory signaling in immune effect cells and its plasma levels are negatively correlated with the occurrence of cardiovascular diseases. Numerous efforts have been made to increase circulating HDL levels or improve HDL functions. In this study, we assessed the effect of synthetic HDL (sHDL) ETC642, a second generation of sHDL, on endotoxin-induced inflammatory cytokine production in macrophages and the underlying mechanism. We first calculated the binding of ETC642 to endotoxins via computer simulation which shows that ETC642 is capable of binding to both LPS and LTA. We next investigated the effect of ETC642 on LPS/LTA-induced NF-κB activation using HEK-Blue cells stably expressing either human TLR-4 or TLR-2. We observed that ETC642 effectively suppressed LPS/LTA-induced NF-κB activation in a dose-dependent manner. We further observed that pre-incubation of the HEK-Blue cells with ETC642 partly suppressed LPS/LTA-induced NF-κB activation, indicating that ETC642 not only neutralized LPS/LTA but also suppressed TLR4- or TLR2-NF-kB signaling. We demonstrated that ETC642 regulates the TLR signaling through modulation of TLR4- or TLR2 to lipid rafts. We finally confirmed the effect of ETC642 in RAW cells and in bone marrow-derived macrophages.