CONTROL OF ENDOTHELIAL-LEUKOCYTE ADHESION MOLECULES BY FATTY-ACIDS

Dietary balance of long-chain fatty acids (FA) I may influence human s usceptibility to pathological processes which involve the interaction of leukocytes with vascular endothelium, such as atherogenesis and inf lammation. Such interaction is largely mediated by the de novo or incr eased expression of endothelial leukocyte adhesion molecules on vascul ar endothelial cells, able to tether and stably bind leukocytes onto t he vessel wall, and by the production of leukocyte chemoattractants. E ndothelial cells do not normally support high levels of leukocyte adhe sion. They do so, however, when exposed to a number of stimuli, such a s oxidized low density lipoprotein bacterial lipopolysaccharides, and inflammatory cytokines, which induce phenotypic changes generally refe rred to as ''endothelial activation.'' We compared various FA in their ability to modulate endothelial activation by cytokines. FA included linoleic, arachidonic, oleic, eicosapentaenoic and, docosahexaenoic ac id (DHA) as representatives of the n-6, n-3 polyunsaturated FA and of the monounsaturated FA. The n-3 FA DHA, and, to a lesser extent, oleat e, at nutritionally compatible concentrations, were able to reduce end othelial expression of Vascular Cell and Adhesion Molecule-1 (VCAM-1). In further studies, DHA dose- and time-dependently reduced also the e xpression of E-selectin, Intercellular Adhesion Molecule-1, interleuki n (IL)-6 and IL-8, in response to IL-l, IL-4, tumor-necrosis factor, o r bacterial endotoxin. The magnitude of this effect paralleled its inc orporation into cellular phospholipids. Also, coordinate with reduced surface adhesion molecule expression, DHA reduced the adhesion of huma n monocytes and of monocytic U937 cells to cytokine-stimulated endothe lial cells. These effects were accompanied by a quantitatively consist ent reduction in VCAM-1 mRNA, indicating a pretranslational control of adhesion molecule gene expression. These novel properties of FA as mo dulators of endothelial activation may help to explain the influence o f dietary FA intake on atherogenesis and inflammation.