Abstract-Cardiovascular disease is the leading cause of morbidity and mortality in westernized populations. Low levels of ␣-tocopherol (AT) are associated with increased incidence of atherosclerosis and increased intakes appear to be protective. Recently, we showed that supplementation with AT resulted in significant decreases in monocyte superoxide anion release, lipid oxidation, interleukin-1 (IL-1) release, and adhesion to endothelium. The reduction in superoxide and lipid oxidation by AT seemed to be mediated by inhibition of protein kinase C. The aim of this study was to investigate the mechanism(s) by which AT inhibits IL-1 release. Potential mechanisms examined included its effect as an antioxidant and its inhibitory effects on protein kinase C and the cyclooxygenase-lipoxygenase pathways. Although AT decreased superoxide release from activated monocytes, superoxide dismutase and catalase had no effect on IL-1 release. Also, a similar antioxidant, -tocopherol, had no effect on IL-1 release. The protein kinase C inhibitor, bisindolylmaleimide, did not inhibit IL-1 release from activated monocytes, in spite of AT decreasing protein kinase C activity. Leukotriene B 4 , a major product of 5-lipoxygenase, has been shown to augment IL-1 release. In the presence of AT, a significant reduction in leukotriene B 4 and IL-1 levels was observed, which was reversed by the addition of leukotriene B 4 . Similar observations were seen with specific inhibitors of 5-lipoxygenase. The product of cyclooxygenase, prostaglandin E 2 , has been shown to inhibit IL-1 activity in some systems. However, AT had no significant effect on prostaglandin E 2 levels in activated monocytes. In the presence of indomethacin, a cyclooxygenase inhibitor, AT inhibited IL-1 activity. Also, AT had no effect on IL-1 mRNA levels or stability, suggesting a posttranscriptional effect. Thus, in activated human monocytes, AT exerts a novel biological effect of inhibiting the release of the proinflammatory cytokine, IL-1, via inhibition of the 5-lipoxygenase pathway. Key Words: vitamin E Ⅲ cytokine Ⅲ interleukins Ⅲ protein kinase C Ⅲ leukotriene A lthough low levels of ␣-tocopherol (AT) are associated with increased risk for cardiovascular disease, increased intakes appear to be protective. [1][2][3][4][5][6] In addition to AT decreasing the oxidative susceptibility of LDL, 7-9 it could have effects on other crucial cells in atherogenesis, such as monocytes, that could prove beneficial. We previously showed that in vivo supplementation with AT significantly decreases monocyte superoxide anion release, lipid oxidation, interleukin-1 (IL-1) release, and adhesion to endothelial cells. 10 In that study it appeared that the inhibition of superoxide anion release and lipid oxidation was mediated by inhibition of protein kinase C (PKC) by AT. However, we did not investigate the mechanism(s) by which AT inhibits IL-1 release and monocyte-endothelial cell adhesion. Recently, we showed that AT enrichment of monocytes decreased agonist-induced adhe...