Soluble CD14 acts as a shuttle in the neutralization of lipopolysaccharide (LPS) by LPS-binding protein and reconstituted high density lipoprotein.

Abstract

SummaryWe have recently shown that lipopolysaccharide (LPS)-binding protein (LBP) is a lipid transfer protein that catalyzes two distinct reactions: movement of bacterial LPS (endotoxin) from LPS micelles to soluble CD14 (sCD14) and movement of LPS from micelles to reconstituted high density lipoprotein (R-HDL) particles. Here we show that LBP facilitates a third lipid transfer reaction: movement of LPS from LPS-sCD14 complexes to R-HDL particles. This action of LBP is catalytic, with one molecule of LBP enabling the movement of multiple LPS molecules into R-HDL. LBP-catalyzed movement of LPS from LPS-sCD14 complexes to R-HDL neutralizes the capacity of LPS to stimulate polymorphonuclear leukocytes. Our findings show that LPS may be transferred to R-HDL either by the direct action of LBP or by a two-step reaction in which LPS is first transferred to sCD14 and subsequently to R-HDL We have observed that the two-step pathway of LPS transfer to R-HDL is strongly favored over direct transfer. Neutralization of LPS by LBP and R-HDL was accelerated more than 30-fold by addition of sCD14. Several observations suggest that sCD14 accelerates this reaction by serving as a shuttle for LPS: addition of LBP and sCD14 to LPS micelles resulted in LPS-sCD14 complexes that could diffuse through a 100-kD cutoff filter; LPS-sCD14 complexes appeared transiently during movement of LPS to R-HDL facilitated by purified LBP; and sCD14 could facilitate transfer of LPS to R-HDL without becoming part of the final LPS-R-HDL complex. Complexes of LPS and sCD14 were formed transiently when LPS was incubated in plasma, suggesting that these complexes may play a role as intermediates in the neutralization of LPS under physiological conditions. These findings detail a new activity for sCD14 and suggest a novel mechanism for lipid transfer by LBP.

Effect of CD14 promoter polymorphism andH. pyloriinfection and its clinical outcomes on circulating CD14

“…There are controversial reports of the linkage between H. pylori infection and atherosclerosis [18]. sCD14 contributes to lipid metabolism, as sCD14 transports lipids and LPS to high-density lipoprotein (HDL) [31,32]. Dysfunctional lipid metabolism is a characteristic feature of several infections [33].…”

Heat shock protein 90 mediates macrophage activation by Taxol and bacterial lipopolysaccharide

“…The interaction of geldanamycin with Hsp 90 causes some signaling molecules to be displaced and adopt an inactivatable conformation (31,32). teins, or bound to soluble CD14, is transferred monomerically to cell-surface CD14 by the enzyme LPS-binding protein (36)(37)(38). Three processes ensue whose mutual relationship is undefined, although each is essential for LPS signaling and each is lps gene-dependent.…”

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…Contrasting data, however, were obtained for a cohort of ART-naïve HIV/ HCV-coinfected patients with high CD4 ϩ T-cell counts, for whom higher sCD14 levels were independently associated with a decreased risk of liver disease progression, defined as a time to Fibrosis 4 (Fib-4) score of Ͼ1.45 or liver-related death. Since sCD14 prevents the interaction of LPS with membrane-bound CD14 on the surface of phagocytes, thus hampering the inflammatory response (138), those authors proposed a model in which high sCD14 levels preserve liver function through the downregulation of the LPS-induced downstream inflammatory cascade (139).…”