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(Circulation Research. 1997;80:149-158.)
© 1997 American Heart Association, Inc.

Articles

Inhibition of Stimulus-Induced Endothelial Cell Intercellular Adhesion Molecule-1, E-Selectin, and Vascular Cellular Adhesion Molecule-1 Expression by Arachidonic Acid and Its Hydroxy and Hydroperoxy Derivatives

Z. Hua Huang, Edna J. Bates, Judith V. Ferrante, Charles S.T. Hii, Alf Poulos, Brenton S. Robinson, Antonio Ferrante

Department of Immunopathology and University of Adelaide Department of Paediatrics (Z.H.H., E.J.B., J.V.F., C.S.T.H., B.S.R, A.F.), and the Department of Chemical Pathology (A.P., B.S.R.), Women's and Children's Hospital, North Adelaide, South Australia.

Correspondence to Prof A. Ferrante, Department of Immunopathology, Women's and Children's Hospital, 72 King William Rd, North Adelaide, South Australia 5006.

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- (TNF-) 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-–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-–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- 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- receptor binding level. The 15-HPETE was found to inhibit the TNF-–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.

Key Words: hydroperoxyeicosatetraenoic acid • monohydroxyeicosatetraenoic acid • 20:4(n-6) • adhesion molecule-1 • endothelial cell

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