13-HPODE and 13-HODE modulate cytokine-induced expression of endothelial cell adhesion molecules differently.
Expression of cellular adhesion molecules (CAMs) at endothelial surfaces represents a physiological response to vascular damage and mediates the initiation of inflammation and possibly of atherogenesis. The cytokines TNF alpha and IL-1 are potent inducers of CAMs in endothelial cells. Reactive oxygen species comprising lipid oxidation products have been implicated in the signaling pathways of both TNF alpha and IL-1 and accordingly could modulate atherogenic events. We, therefore, investigated the potential role of the lipoxygenase product, 13-hydroperoxyoctadecadienoic acid (13-HPODE), which has also been identified in oxidized low density lipoproteins on CAM expression in HUVEC. 13-HPODE induced the expression of ICAM-1 in a concentration dependent manner up to 75 microM. Higher concentrations were toxic. Similar effects were observed with H2O2 and phosphatidylcholine hydroperoxide. VCAM-1 and E-selectin were not induced by 13-HPODE. 13-HPODE administered simultaneously with IL-1 or TNF alpha induced ICAM-1 additively, suggesting that hydroperoxides and cytokines act on the same signaling pathways. In contrast, pretreatment of cells with 50 microM 13-HPODE for 1 hour rather inhibited subsequent cytokine-induced ICAM-1 and E-selectin expression. Surprisingly, the reduction product of 13-HPODE, 13-hydroxyoctadecadienoic acid (13-HODE) proved to be an even better inducer of ICAM-1 than 13-HPODE. Pretreatment with 13-HODE did not show any inhibitory effect on ICAM-1 expression. Our data show that lipoxygenase products differentially affect CAM expression. 13-HPODE is stimulatory by itself and can positively or negatively affect cytokine signaling depending on time of exposure. 13-HODE induces CAM expression by itself but does not inhibit cytokine signaling. Thus, the interplay of lipoxygenase products with proinflammatory cytokines can not simply be explained by an oxidant-mediated facilitation of cytokine signaling.
Friedrichs
B
B
German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany.
Toborek
M
M
Hennig
B
B
Heinevetter
L
L
Müller
C
C
Brigelius-Flohé
R
R
D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008041:Linoleic Acids / Q000494:pharmacology*; D008054:Lipid Peroxides / Q000494:pharmacology*; D010713:Phosphatidylcholines / Q000494:pharmacology; D019163:Reducing Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014470:Umbilical Cord / Q000166:cytology; D015854:Up-Regulation / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D015815:Cell Adhesion Molecules; D016207:Cytokines; D019040:E-Selectin; D008041:Linoleic Acids; D008054:Lipid Peroxides; D010713:Phosphatidylcholines; D019163:Reducing Agents; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C057590:phosphatidylcholine hydroperoxide; D018799:Intercellular Adhesion Molecule-1; C038649:13-hydroperoxy-9,11-octadecadienoic acid; C024348:13-hydroxy-9,11-octadecadienoic acid; D006861:Hydrogen Peroxide