alpha-tocopherol decreases interleukin-1 beta release from activated humanmonocytes by inhibition of 5-lipoxygenase

Cardiovascular disease is the leading cause of morbidity and mortality in w esternized populations. Low levels of alpha-tocopherol (AT) are associated with increased incidence of atherosclerosis and increased intakes appear to be protective. Recently, we showed that supplementation with AT resulted i n significant decreases in monocyte superoxide anion release, lipid oxidati on, interleukin-1 beta (IL-1 beta) release, and adhesion to endothelium. Th e reduction in superoxide and lipid oxidation by AT seemed to be mediated b y inhibition of protein kinase C. The aim of this study was to investigate the mechanism(s) by which AT inhibits IL-1 beta release. Potential mechanis ms examined included its effect as an antioxidant and its inhibitory effect s on protein kinase C and. the cyclooxygenase-lipoxygenase pathways. Althou gh AT decreased superoxide release from activated monocytes, superoxide dis mutase and catalase had no effect on IL-1 beta release. Also, a similar ant ioxidant, beta-tocopherol, had no effect on IL-1 beta release. The protein kinase C inhibitor, bisindolylmaleimide, did not inhibit IL-1 beta release from activated monocytes, in spite of AT decreasing protein kinase C activi ty. Leukotriene B-4, a major product of 5-lipoxygenase, has been shown to a ugment IL-1 beta release. In the presence of AT, a significant reduction in leukotriene B-4 and IL-1 beta levels was observed, which was reversed by t he addition of leukotriene Bq Similar observations were seen with specific inhibitors of S-lipoxygenase. The product of cyclooxygenase, prostaglandin E-2, has been shown to inhibit IL-1 beta activity in some systems. However, AT had no significant effect on prostaglandin E-2 levels in activated mono cytes. In the presence of indomethacin, a cyclooxygenase inhibitor, AT inhi bited IL-1 beta activity. Also, AT had no effect on IL-1 beta mRNA levels o r stability, suggesting a posttranscriptional effect. Thus, in activated hu man monocytes, AT exerts a novel biological effect of inhibiting the releas e of the proinflammatory cytokine, IL-1 beta, via inhibition of the 5-lipox ygenase pathway.