α-Tocopherol Inhibits IL-8 Synthesis Induced by Thrombin and High Glucose in Endothelial Cells

Abstract

It has been reported that α-tocopherol, an antioxidant agent, may play a role in preventing diabetic angiopathy. However, there is little evidence to show the effect of α-tocopherol on the production of pro-inflammatory cytokines in endothelial cells. Therefore, we examined the effect of α-tocopherol on the regulation of IL-8 synthesis induced by high glucose and/or thrombin in endothelial cells. Thrombin alone markedly increased the IL-8 release. Furthermore, high glucose levels and thrombin combined had additive effects on IL-8 synthesis, and α-tocopherol diminished their effect; α-tocopherol also inhibited the phosphorylation of IκB-α induced by high glucose levels and/or thrombin. Our results suggest that the administration of α-tocopherol to diabetic patients may have a beneficial effect for the prevention of diabetic vascular complications by the inhibition of IL-8 synthesis from endothelial cells.

Anti-Oxidant - High Glucose - Diabetic Angiopathy - Signal Transduction

References

• 1 Brand F N, Abbott R D, Kannel W B. Diabetes, intermittent claudication, and risk of cardiovascular events. The Framingham Study.  Diabetes. 1989;  38 504-509
• 2 Stamler J, Vaccaro O, Neaton J D, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.  Diabetes Care. 1993;  16 434-444
• 3 Ruderman N B, Haudenschild C. Diabetes as an atherogenic factor.  Pro Cardiovasc Dis. 1984;  26 373-412
• 4 Freitas J P, Filipe P M, Rodrigo F G. Lipid peroxidation in type 2 normolipidemic diabetic patients.  Diabetes Res Clin Pract. 1997;  36 71-75
• 5 Li A E, Ito H, Rovira I I, Kim K S, Takeda K, Yu Z Y, Ferrans V J, Finkel T. A role for reactive oxygen species in endothelial cell anoikis.  Circ Res. 1999;  85 304-1021
• 6 Laight D W, Carrier M J, Anggard E E. Antioxidants, diabetes and endothelial dysfunction.  Cardiovasc Res. 2000;  47 457-464
• 7 Nishikawa T, Edelstein D, Brownlee M. The missing link: a single unifying mechanism for diabetic complications.  Kidney Int. 2000;  58 Suppl. 77 S26-30
• 8 Libby P, Loppnow H, Fleet J C. et al . Production of cytokines by vascular wall cells: An update and implications for atherogenesis. In: Gotlieb AI, Langille BL, Fedoroff S (eds) Atherosclerosis - Cellular and Molecular Interactions in the Artery Wall. New York & London; Plenum Press 1991: 161-169
• 9 Matsushima K, Morishita K, Yoshimura T, Lavu S, Kobayashi Y, Lew W, Appella E, Kung H F, Leonard E J, Oppenheim J J. Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin-1 and tumor necrosis factor.  J Exp Med. 1988;  167 1883-1893
• 10 Yue T L, Mckenna P J, Gu J L, Feuerstein G Z. Interleukin-8 is chemotactic for vascular smooth muscle cells.  Eur J Pharmacol. 1993;  240 81-84
• 11 Wang N, Tabas I, Winchester R, Ravalli S, Rabbani L E, Tall A. Interleukin-8 is induced by cholesterol loading of macrophages and expressed by macrophage foam cells in human atheroma.  J Biol Chem. 1996;  271 8837-8842
• 12 Urakaze M, Temaru R, Satou A, Yamazaki K, Hamazaki T, Kobayashi M. The IL-8 production in endothelial cells is stimulated by high glucose.  Horm Metab Res. 1996;  28 400-401
• 13 Rimm E B, Stampfer M J, Ascherio A, Giovannucci E, Colditz G A, Willett W C. Vitamin E consumption and the risk of coronary heart disease in men.  N Engl J Med. 1993;  328 1450-1456
• 14 Riemersma R A, Wood D A. et al . Risk of angina pectoris and plasma concentrations of vitamins A, C, and E, and carotene.  Lancet. 1991;  337 1-5
• 15 Ness A, Smith G D. Mortality in the CHAOS trial. Cambridge Heart Antioxidant Study.  Lancet. 1999;  353 1017-1018
• 16 Temaru R, Urakaze M, Satou A, Yamazaki K, Nakamura N, Kobayashi M. High glucose enhances the gene expression of interleukin-8 in human endothelial cells, but not in smooth muscle cells: possible role of interleukin-8 in diabetic macroangiopathy.  Diabetologia. 1997;  40 610-613
• 17 Luster A D. Chemokines-chemotactic cytokines that mediate inflammation.  N Engl J Med. 1998;  338 436-445
• 18 Yue T L, Wang X, Sung C P. et al . Interleukin-8: a mitogen and chemoattractant for vascular smooth muscle cells.  Circ Res. 1994;  75 1-7
• 19 Huber A R, Kunkel S L, Todd R F, Weiss S J. Regulation of transendothelial neutrophil migration by endogenous interleukin-8.  Science. 1992;  254 99-102
• 20 Rus H G, Vlaicu R, Niculescu F. Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall.  Atherosclerosis. 1996;  127 263-271
• 21 Roebuck K A. Oxidant stress regulation of IL-8 and ICAM-1 gene expression: differential activation and binding of the transcription factors AP-1 and NF-kappa B (Review).  Int J Mol Med. 1999;  4 223-230
• 22 Devaraj S, Jialal I. Low-density lipoprotein post-secretary modification, monocyte function, and circulating adhesion molecules in type 2 diabetic patients with and without macrovascular complications: the effect of alpha-tocopherol supplementation.  Circulation. 2000;  102 191-196
• 23 Ferber P, Moll K, Koschinsky T, Rosen P, Susanto F, Schwippert B, Tschope D. High dose supplementation of RRR-alpha-tocopherol decreases cellular hemostasis but accelerates plasmatic coagulation in type 2 diabetes mellitus.  Horm Metab Res. 1999;  31 665-671
• 24 Inoguchi T, Battan R, Handler E, Sportsman J R, Heath W, King G L. Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation.  Proc Natl Acad Sci USA. 1992;  89 11 059-11 063
• 25 King G L, Shiba T, Oliver J, Inoguchi T, Bursell S E. Cellular and molecular abnormalities in the vascular endothelium of diabetes mellitus.  Annu Rev Med. 1994;  45 179-188
• 26 Lee I K, Koya D, Ishii H, Kanoh H, King G L. d-Alpha-tocopherol prevents the hyperglycemia induced activation of diacylglycerol (DAG)-protein kinase C (PKC) pathway in vascular smooth muscle cell by an increase of DAG kinase activity.  Diabetes Res Clin Pract. 1999;  45 183-190
• 27 Schoonbroodt S, Piette J. Oxidative stress interference with the nuclear factor- kappa B activation pathways.  Biochem Pharmacol. 2000;  60 1075-1083
• 28 Li D, Saldeen T, Mehta J L. Effects of alpha-tocopherol on ox-LDL-mediated degradation of IkappaB and apoptosis in cultured human coronary artery endothelial cells.  J Cardiovasc Pharmacol. 2000;  36 297-301
• 29 Cominacini L, Garbin U, Pasini A F, Davoli A, Campagnola M, Rigoni A, Tosetti L, Lo Cascio V. The expression of adhesion molecules on endothelial cells is inhibited by troglitazone through its antioxidant activity.  Cell Adhes Commun. 1999;  7 223-231