Low density lipoproteins inhibit endotoxin activation of monocytes.

Abstract

Human serum and low density lipoproteins (LDLs) were shown to inactivate endotoxin (lipopolysaccharide [IPS]) by testing the effect of LPS interactions with serum or LDL on the activation of human monocytes. Sera and LDL preparations from four patients with familial hypercholesterolemia were used to demonstrate the inhibition of LPS from inducing interleukin-1 release. Before LDL removal by immunoapheresis, the patients' sera were able to inactivate approximately fivefold more LPS than after LDL removal. The LPS-inactivating capacity lost during apheresis could essentially be retrieved in the LDL-rich eluate from the immunoadsorption columns. Because patients were treated frequently with immunoapheresis, their LDL levels before LDL removal were not markedly elevated. These patients' sera before LDL removal were shown to inactivate amounts of LPS comparable to those inactivated by the sera from three healthy volunteers. LDL prepared by ultracentrifugation showed similar LPS inactivation as LDL prepared by immunoapheresis. We conclude that the inhibition of LPS-induced monocyte activation by human serum is dependent to a large extent on the LDL fraction. LDLs were demonstrated to inhibit LPS from inducing interleukin-1 release by human monocytes. ( 1 -3 Lipoproteins were recently shown to diminish the biologic activity of LPS with respect to human monokine release. -5 In humans, low density lipoproteins (LDLs) may bind more LPS than do high density lipoproteins.6 It was not known whether changes in the lipoprotein content of serum would influence the inhibitory effect of serum on LPSinduced monokine release and the extent of LDL involvement.In patients with familial hypercholesterolemia, the excessive content of LDL in serum is caused by defective LDL receptors. The LDL particles themselves, however, are not aberrant.7 Because marked changes in This study was undertaken to investigate the effect of changes in LDL content of human serum on LPS inactivation. In addition, human LDLs could be tested for their participation in LPS inactivation with regard to human monokine release. Methods PatientsThree female (25, 43, and 51 years old) and one male (48 years old) patient were studied, all having heterozygous familial hypercholesterolemia with hyperlipoproteinemia type Ila. Diagnoses were established in adulthood in all patients. The patients were treated once a week with LDL apheresis 1011 for 1-3 years, using immunoadsorption columns carrying anti-apolipoprotein (apo) B antibody (LDL-Therasorb, Baxter, Munich, FRG) to reduce serum cholesterol levels to 3.9 mmol/1 or less after treatment. For this study, an additional 20 ml of blood was drawn from the patients before and after LDL apheresis, but no changes in the procedure of the LDL apheresis therapy were made. Informed consent was obtained in accordance with regulations set by the ethics commission of the medical faculty of the University of

Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock

“…The in vitro data mainly parallel those found in vivo. These data confirm that binding of LPS to lipoproteins decreases its ability to activate macrophages and endothelial cells (30,57,60,196,306,366,415,554,579) (Table 5). Recently, Grunfeld et al have shown a similar inhibitory effect of lipoprotein binding on LTA-induced activation of macrophages (177).…”

Hyperlipidemia-Induced MicroRNA-155-5p Improves β-Cell Function by TargetingMafb

“…LPS predominantly binds to LDL in the circulation, which reduces its biological activity and promotes endotoxin removal. 135,[187][188][189][190][191] The data of the current study show that mild oxidation increases the endotoxin activity of LDL, maybe by altering lipid-mediated interactions between LDL and LPS. Accordingly, treatment with moxLDL but not with nLDL upregulated miR-155-5p expression in β-cells.…”

Consequences of Interaction of a Lipophilic Endotoxin Antagonist with Plasma Lipoproteins

“…It has also become clear that LPS is moved into serum lipoproteins by lipid transferases, resulting in a loss of agonistic potency (9,10,13,21,31,35). E5531 is a lipophilic molecule that lacks the complex polysaccharide of LPS.…”