Localized adhesion of peripheral blood leukocytes to the endothelial lining is essential for their exit from the blood under both physiological and pathological conditions. The establishment, development, and resolution of the inflammatory response is regulated by an array of mediators, many of which remain to be categorized. These include
arachidonic acid (20:4n-6) and its hydroperoxy (HPETE) and hydroxy (
HETE) derivatives, which are released during
inflammation. The data show that human umbilical vein endothelial cells, pretreated with these
fatty acids, have a reduced ability to be stimulated by
tumor necrosis factor-alpha (
TNF-alpha) for enhanced neutrophil and monocyte adhesion; the order of inhibitory activity being
15-HPETE >
15-HETE > 20:4 (n-6). This
fatty acid-induced inhibitory activity was reflected in the ability of the mediators to decrease the
TNF-alpha-induced expression of the following endothelial
adhesion molecules: intercellular adhesion molecule-1 (ICAM-1),
E-selectin, and
vascular cell adhesion molecule-1 (VCAM-1), measured by both
enzyme-linked
immunosorbent assay and flow cytometric analysis.
TNF-alpha-induced increased expression of
ICAM-1,
E-selectin, and
VCAM-1 mRNA was significantly depressed by
15-HPETE. Constitutively expressed
ICAM-1 and
ICAM-1 mRNAs were unchanged by the
fatty acids. The
saturated fatty acid 20:0 and the methyl
ester of 20:4(n-6) had no inhibitory activity. The binding of
TNF-alpha to its receptors was not altered by these
fatty acids. The
fatty acids also inhibited the expression of
ICAM-1 and
E-selectin induced by
phorbol 12-myristate 13-acetate, showing that inhibition occurred at a post-
TNF-alpha receptor binding level. The
15-HPETE was found to inhibit the
TNF-alpha-induced increase in adhesion molecule expression in the early stage of the incubation, but expression returned to normal after 18 hours. An effect of
15-HPETE on the early cell signaling system was demonstrated by the ability of this
fatty acid to inhibit agonist-induced
protein kinase C translocation.