α-Tocopherol decreases interleukin-1β release from activated human monocytes by inhibition of 5-lipoxygenase

Sridevi Devaraj, Ishwarlal Jialal

Research output: Contribution to journalArticle

141 Scopus citations

Abstract

Cardiovascular disease is the leading cause of morbidity and mortality in westernized populations. Low levels of α-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-1β (IL-1β) 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-1β 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-1β release. Also, a similar antioxidant, β-tocopherol, had no effect on IL-1β release: The protein kinase C inhibitor, bisindolylmaleimide, did not inhibit IL-1β release from activated monocytes, in spite of AT decreasing protein kinase C activity. Leukotriene B4, a major product of 5-lipoxygenase, has been shown to augment IL-1β release. In the presence of AT, a significant reduction in leukotriene B4 and IL-1β levels was observed, which was reversed by the addition of leukotriene B4. Similar observations were seen with specific inhibitors of 5-lipoxygenase. The product of cyclooxygenase, prostaglandin E2, has been shown to inhibit IL-1β activity in some systems. However, AT had no significant effect on prostaglandin E2 levels in activated monocytes. In the presence of indomethacin, a cyclooxygenase inhibitor, AT inhibited IL-1β activity. Also, AT had no effect on IL-1β 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-1β, via inhibition of the 5-lipoxygenase pathway.

Original languageEnglish (US)
Pages (from-to)1125-1133
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume19
Issue number4
StatePublished - Apr 1999
Externally publishedYes

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Keywords

  • Cytokine
  • Interleukins
  • Leukotriene
  • Protein kinase C
  • Vitamin E

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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