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Alpha-tocopherol decreases interleukin-1 beta release from activated human monocytes by inhibition of 5-lipoxygenase
1Center for Human Nutrition, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Insights
Alpha-tocopherol (AT) inhibits the release of the inflammatory cytokine interleukin-1 beta (IL-1 beta) by affecting the 5-lipoxygenase pathway in human monocytes. This finding offers new insights into cardiovascular disease prevention strategies.
Area of Science:
- Biochemistry
- Immunology
- Nutritional Science
Background:
- Cardiovascular disease is a leading cause of death in Western populations.
- Low alpha-tocopherol (AT) levels are linked to increased atherosclerosis risk.
- Previous studies indicated AT supplementation reduces monocyte inflammatory responses.
Purpose of the Study:
- To elucidate the mechanisms by which alpha-tocopherol (AT) inhibits interleukin-1 beta (IL-1 beta) release.
- To investigate AT's roles as an antioxidant and its effects on protein kinase C and eicosanoid pathways.
Main Methods:
- Activated human monocytes were treated with AT.
- Assays measured superoxide anion release, lipid oxidation, IL-1 beta levels, and eicosanoid production (leukotriene B4, prostaglandin E2).
- Inhibition studies involved specific pathway inhibitors and complementary substances.
Main Results:
- AT inhibited IL-1 beta release, primarily through the 5-lipoxygenase pathway, evidenced by reduced leukotriene B4.
- AT's antioxidant and protein kinase C inhibitory effects were not the primary mechanism for IL-1 beta inhibition.
- AT did not affect IL-1 beta mRNA levels, indicating a post-transcriptional regulatory mechanism.
Conclusions:
- Alpha-tocopherol (AT) inhibits the release of the pro-inflammatory cytokine IL-1 beta in activated human monocytes.
- This inhibition is mediated by the 5-lipoxygenase pathway, representing a novel biological effect of AT.
- Findings suggest AT's potential role in managing inflammatory processes relevant to cardiovascular health.
Abstract:
Cardiovascular disease is the leading cause of morbidity and mortality in westernized 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 in significant decreases in monocyte superoxide anion release, lipid oxidation, interleukin-1 beta (IL-1 beta) 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 beta 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 beta release. Also, a similar antioxidant, 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 activity. Leukotriene B4, a major product of 5-lipoxygenase, has been shown to augment IL-1beta release. In the presence of AT, a significant reduction in leukotriene B4 and IL-1 beta 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-1 beta 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-1 beta activity. Also, AT had no effect on IL-1 beta 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 beta, via inhibition of the 5-lipoxygenase pathway.