© 1999 American Heart Association, Inc.
Original Contributions |
-Tocopherol Decreases Interleukin-1ß Release From Activated Human Monocytes by Inhibition of 5-Lipoxygenase
From the Center for Human Nutrition (S.D., I.I.) and Departments of Pathology (S.D., I.J.) and Internal Medicine (I.J.), University of Texas Southwestern Medical Center, Dallas, Tex.
Correspondence to I. Jialal, MD, PhD, Department of Internal Medicine and Pathology, The University of Texas Southwestern Medical Center at Dallas Dallas, TX 75235-9073. E-mail jialal.i{at}pathology.swmed.edu
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-1ß (IL-1ß)
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-1ß 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-1ß release. Also, a similar antioxidant,
ß-tocopherol, had no effect on IL-1ß release. The
protein kinase C inhibitor, bisindolylmaleimide, did not
inhibit IL-1ß 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-1ß release. In the presence of AT, a
significant reduction in leukotriene B4 and
IL-1ß 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-1ß 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-1ß activity. Also, AT had no effect on IL-1ß 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-1ß, via inhibition of the 5-lipoxygenase pathway.
Key Words: vitamin E • cytokine • interleukins • protein kinase C • leukotriene
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