Comparison of Three Tocopherol Analogs as an Inhibitor of Production of Proinflammatory Mediators in Macrophages

Anti-inflammatory effects of tocopherol (TOL) analogs have been attributed to their potent antioxidant activities. However, we and others have separately reported that gamma TOL or alpha-tocopheryl succinate (alpha TOS), despite their lower antioxidant activities, inhibit lipopolysaccharide (LPS)-induced production of prostaglandin E-2 (PGE(2)) in macrophages and lung epithelial cells more effectively than alpha TOL. In the present study, we sought to directly analyze the effect of three TOL analogs (alpha TOL, alpha TOS, and gamma TOL) on LPS-induced production of pro-inflammatory mediators in macrophages. Our data demonstrated that the inhibitory effects of all three TOL analogs on nitric oxide production were very limited. In contrast, alpha TOS dose-dependently and significantly inhibited LPS-induced PGE(2) production in both RAW264.7 cells and peritoneal macrophages, whereas alpha TOL and gamma TOL were much less effective. Although alpha TOS had no effect on LPS-induced cyclooxygenase-2 expression, it did inhibit COX activity in intact cells. alpha TOS in combination with sulforaphane, a compound that blocked LPS-induced COX-2 expression, cooperatively and more significantly inhibited PGE(2) production. These findings suggest that alpha TOS is a more potent inhibitor of the pro-inflammatory mediator PGE(2). The inclusion of alpha TOS in vitamin supplements may further enhance the effectiveness of strategies for preventing diseases associated with inflammation.