Synergistic inhibition of cyclooxygenase-2 expression by vitamin E and aspirin.
The use of aspirin in rheumatoid arthritis is limited since inhibition of the pro-inflammatory enzyme cyclooxygenase-2 occurs only at higher aspirin doses that are often associated with side effects such as gastric toxicity. Using a macrophage cell line (J774. 1A), the present study explores possible synergistic effects of aspirin and vitamin E on the expression and activity of cyclooxygenase-2. Lipopolysaccharide-induced prostaglandin E(2) formation was significantly reduced by aspirin (1-100 microM) or vitamin E (100-300 microM). When combined with vitamin E, aspirin-dependent inhibition of prostaglandin E(2) formation was increased from 59% to 95% of control. Likewise, lipopolysaccharide-induced cyclooxygenase-2 protein and mRNA expression were virtually abolished by the combined treatment of aspirin and vitamin E, whereas the two agents alone were only modestly effective. Vitamin C did not mimic the actions of vitamin E under these conditions, suggesting that redox-independent mechanisms underlie the action of vitamin E. In agreement with this, vitamin E and aspirin were without effect on lipopolysaccharide-induced translocation of the redox-sensitive transcription factor NF-kappa B. Our results show that co-administration of vitamin E renders cyclooxygenase-2 more sensitive to inhibition by aspirin by as yet unknown mechanisms. Thus, anti-inflammatory therapy might be successful with lower aspirin doses when combined with vitamin E, thereby possibly avoiding the side effects of the usually required high dose aspirin treatment.
Abate
A
A
Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Halle (Saale), Germany.
Yang
G
G
Dennery
P A
PA
Oberle
S
S
Schröder
H
H
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D002460:Cell Line; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects*; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D014810:Vitamin E / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D014810:Vitamin E; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001205:Ascorbic Acid; D001241:Aspirin