Synergistic inhibition of cyclooxygenase-2 expression by vitamin E and aspirin

The use of aspirin in rheumatoid arthritis is limited since inhibition of t he pro-inflammatory enzyme cyclooxygenase-2 occurs only at higher aspirin d oses 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 activit y of cyclooxygenase-2. Lipopolysaccharide-induced prostaglandin E-2 formati on was significantly reduced by aspirin (1-100 muM) or vitamin E (100-300 m uM). When combined with vitamin E-,E- aspirin-dependent inhibition of prost aglandin E-2 formation was increased from 59% to 95% of control. Likewise, lipopolysaccharide-induced cyclooxygenase-2 protein and mRNA expression wer e virtually abolished by the combined treatment of aspirin and vitamin E, w hereas the two agents alone were only modestly effective. Vitamin C did not mimic the actions of vitamin E under these conditions, suggesting that red ox-independent mechanisms underlie the action of vitamin E. In agreement wi th this, vitamin E and aspirin were without effect on lipopolysaccharide-in duced translocation of the redox-sensitive transcription factor NF-kappa B. Our results show that co-administration of vitamin E renders cyclooxygenas e-2 more sensitive to inhibition by aspirin by as yet unknown mechanisms. T hus, anti-inflammatory therapy might be successful with lower aspirin doses when combined with vitamin E, thereby possibly avoiding the side effects o f the usually required high dose aspirin treatment. (C) 2000 Elsevier Scien ce Inc.