Linoleic acid and TNF-alpha cross-amplify oxidative injury and dysfunction of endothelial cells.
Factors implicated in the development of atherosclerosis include metabolic alterations of the endothelium induced by certain lipids and inflammatory cytokines. To study the hypothesis that the combined presence of unsaturated fatty acids and inflammatory cytokines may cross-amplify their individual injurious effects, cultured endothelial cells were treated with 90 mu M of linoleic acid (18:2 n-6) and/or 20 ng/ml (100 U/ml) of tumor necrosis factor-alpha (TNF) for up to 24 h. Disturbances in endothelial cell metabolism were determined by measuring cellular oxidative stress, oxidative stress-inducible nuclear factor-kappa B (NF-kappa B) and NF-kappa B-related transcription, intracellular calcium levels, and endothelial barrier function reflected by transendothelial albumin movement. Both 18:2 and TNF increased cellular oxidation, intracellular calcium, and endothelial barrier permeability. These changes were cross-amplified in cells treated both with 18:2 and TNF, compared with 18:2 or TNF alone. In contrast, a combined exposure to 18:2 and TNF did not potentiate effects mediated by 18:2 or TNF alone on NF-kappa B activation or NF-kappa B-related transcription. Pretreatment with 25 mu M vitamin E attenuated 18:2 and/or TNF-mediated endothelial cell dysfunction. These results suggest that certain unsaturated fatty acids can potentiate TNF-mediated endothelial cell dysfunction and that oxidative stress may be partially responsible for these metabolic events. These findings have implications for understanding lipid-mediated inflammatory responses in atherosclerosis.
Toborek
M
M
Departments of Nutrition and Food Science, University of Kentucky, Lexington 40506-0054, USA.
Barger
S W
SW
Mattson
M P
MP
Barve
S
S
McClain
C J
CJ
Hennig
B
B
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011651:Pulmonary Artery / Q000166:cytology; D013552:Swine; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014810:Vitamin E / Q000494:pharmacology
D008041:Linoleic Acids; D014409:Tumor Necrosis Factor-alpha; D014810:Vitamin E; D019787:Linoleic Acid