Adhesion and recruitment of blood monocytes, processes mediated by
cell adhesion molecules including
E-selectin, represent an early event in
atherogenesis.
High density lipoproteins (HDLs) were shown to inhibit
cytokine-induced expression of adhesion molecules, but mechanisms underlying this effect are not fully understood. We here investigated the effects of
sphingosylphosphorylcholine (SPC) and
lysosulfatide (LSF), two
lysosphingolipids associated with HDL, on
TNF-alpha-induced
E-selectin expression in human umbilical endothelial cells. We found that HDL, SPC, and LSF inhibited
E-selectin expression both on
mRNA and
protein level. In addition, all three agents reduced the number of
E-selectin molecules present on endothelial cell surface. The inhibitory effects of HDL, SPC, and LSF on
TNF-alpha-induced
E-selectin expression were partially reverted in the presence of
suramin, an antagonist of
lysosphingolipid receptor EDG-3, or
pertussis toxin, an inhibitor of trimeric
G proteins. In addition, inhibition of activation of
protein kinase Akt with
LY294002 but not inhibition of
phosphatidylinositol-specific phospholipase C (PI-PLC) with
U73122 abolished the restrictive effects of HDL-, SPC-, or LSF on
E-selectin expression. We conclude that HDL-associated
lysosphingolipids may at least partially account for the inhibitory effects of HDL on
cytokine-induced expression of adhesion molecules, and that activations of
G-protein-coupled receptors and
protein kinase Akt are involved in this process.