Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Aug 1;98(3):756–763. doi: 10.1172/JCI118848

The effects of alpha tocopherol supplementation on monocyte function. Decreased lipid oxidation, interleukin 1 beta secretion, and monocyte adhesion to endothelium.

S Devaraj 1, D Li 1, I Jialal 1
PMCID: PMC507486  PMID: 8698868

Abstract

Low levels of alpha tocopherol are related to a higher incidence of cardiovascular disease and increased intake appears to afford protection against cardiovascular disease. In addition to decreasing LDL oxidation, alpha tocopherol may exert intracellular effects on cells crucial in atherogenesis, such as monocytes. Hence, the aim of this study was to test the effect of alpha tocopherol supplementation on monocyte function relevant to atherogenesis. Monocyte function was assessed in 21 healthy subjects at baseline, after 8 wk of supplementation with d-alpha tocopherol (1,200 IU/d) and after a 6-wk washout phase. The release of reactive oxygen species (superoxide anion, hydrogen peroxide), lipid oxidation, release of the potentially atherogenic cytokine, interleukin 1 beta, and monocyte-endothelial adhesion were studied in the resting state and after activation of the monocytes with lipopolysaccharide at 0, 8, and 14 wk. There was a 2.5-fold increase in plasma lipid-standardized and monocyte alpha tocopherol levels in the supplemented phase. After alpha tocopherol supplementation, there were significant decreases in release of reactive oxygen species, lipid oxidation, IL-1 beta secretion, and monocyte-endothelial cell adhesion, both in resting and activated cells compared with baseline and washout phases. Studies with the protein kinase C inhibitor, Calphostin C, suggest that the inhibition of reactive oxygen species release and lipid oxidation is due to an inhibition of protein kinase C activity by alpha tocopherol. Thus, this study provides novel evidence for an intracellular effect of alpha tocopherol in monocytes that is antiatherogenic.

Full Text

The Full Text of this article is available as a PDF (210.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams D. H., Shaw S. Leucocyte-endothelial interactions and regulation of leucocyte migration. Lancet. 1994 Apr 2;343(8901):831–836. doi: 10.1016/s0140-6736(94)92029-x. [DOI] [PubMed] [Google Scholar]
  2. Agil A., Fuller C. J., Jialal I. Susceptibility of plasma to ferrous iron/hydrogen peroxide-mediated oxidation: demonstration of a possible Fenton reaction. Clin Chem. 1995 Feb;41(2):220–225. [PubMed] [Google Scholar]
  3. Akeson A. L., Woods C. W., Mosher L. B., Thomas C. E., Jackson R. L. Inhibition of IL-1 beta expression in THP-1 cells by probucol and tocopherol. Atherosclerosis. 1991 Feb;86(2-3):261–270. doi: 10.1016/0021-9150(91)90222-o. [DOI] [PubMed] [Google Scholar]
  4. Baeuerle P. A., Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–179. doi: 10.1146/annurev.iy.12.040194.001041. [DOI] [PubMed] [Google Scholar]
  5. Ball R. Y., Carpenter K. L., Enright J. H., Hartley S. L., Mitchinson M. J. Ceroid accumulation by murine peritoneal macrophages exposed to artificial lipoproteins. Br J Exp Pathol. 1987 Jun;68(3):427–438. [PMC free article] [PubMed] [Google Scholar]
  6. Berkow R. L., Wang D., Larrick J. W., Dodson R. W., Howard T. H. Enhancement of neutrophil superoxide production by preincubation with recombinant human tumor necrosis factor. J Immunol. 1987 Dec 1;139(11):3783–3791. [PubMed] [Google Scholar]
  7. Berliner J. A., Navab M., Fogelman A. M., Frank J. S., Demer L. L., Edwards P. A., Watson A. D., Lusis A. J. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation. 1995 May 1;91(9):2488–2496. doi: 10.1161/01.cir.91.9.2488. [DOI] [PubMed] [Google Scholar]
  8. Boscoboinik D., Szewczyk A., Hensey C., Azzi A. Inhibition of cell proliferation by alpha-tocopherol. Role of protein kinase C. J Biol Chem. 1991 Apr 5;266(10):6188–6194. [PubMed] [Google Scholar]
  9. Boveris A., Martino E., Stoppani A. O. Evaluation of the horseradish peroxidase-scopoletin method for the measurement of hydrogen peroxide formation in biological systems. Anal Biochem. 1977 May 15;80(1):145–158. doi: 10.1016/0003-2697(77)90634-0. [DOI] [PubMed] [Google Scholar]
  10. Burton G. W., Ingold K. U. Vitamin E as an in vitro and in vivo antioxidant. Ann N Y Acad Sci. 1989;570:7–22. doi: 10.1111/j.1749-6632.1989.tb14904.x. [DOI] [PubMed] [Google Scholar]
  11. Burton G. W., Webb A., Ingold K. U. A mild, rapid, and efficient method of lipid extraction for use in determining vitamin E/lipid ratios. Lipids. 1985 Jan;20(1):29–39. doi: 10.1007/BF02534359. [DOI] [PubMed] [Google Scholar]
  12. Carpenter K. L., Ballantine J. A., Fussell B., Enright J. H., Mitchinson M. J. Oxidation of cholesteryl linoleate by human monocyte-macrophages in vitro. Atherosclerosis. 1990 Aug;83(2-3):217–229. doi: 10.1016/0021-9150(90)90167-h. [DOI] [PubMed] [Google Scholar]
  13. Cathcart M. K., Chisolm G. M., 3rd, McNally A. K., Morel D. W. Oxidative modification of low density lipoprotein (LDL) by activated human monocytes and the cell lines U937 and HL60. In Vitro Cell Dev Biol. 1988 Oct;24(10):1001–1008. doi: 10.1007/BF02620873. [DOI] [PubMed] [Google Scholar]
  14. Cathcart M. K., McNally A. K., Morel D. W., Chisolm G. M., 3rd Superoxide anion participation in human monocyte-mediated oxidation of low-density lipoprotein and conversion of low-density lipoprotein to a cytotoxin. J Immunol. 1989 Mar 15;142(6):1963–1969. [PubMed] [Google Scholar]
  15. Esterbauer H., Gebicki J., Puhl H., Jürgens G. The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med. 1992 Oct;13(4):341–390. doi: 10.1016/0891-5849(92)90181-f. [DOI] [PubMed] [Google Scholar]
  16. Faruqi R., de la Motte C., DiCorleto P. E. Alpha-tocopherol inhibits agonist-induced monocytic cell adhesion to cultured human endothelial cells. J Clin Invest. 1994 Aug;94(2):592–600. doi: 10.1172/JCI117374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Galanos C., Lüderitz O., Rietschel E. T., Westphal O., Brade H., Brade L., Freudenberg M., Schade U., Imoto M., Yoshimura H. Synthetic and natural Escherichia coli free lipid A express identical endotoxic activities. Eur J Biochem. 1985 Apr 1;148(1):1–5. doi: 10.1111/j.1432-1033.1985.tb08798.x. [DOI] [PubMed] [Google Scholar]
  18. Gamble J. R., Vadas M. A. A new assay for the measurement of the attachment of neutrophils and other cell types to endothelial cells. J Immunol Methods. 1988 May 9;109(2):175–184. doi: 10.1016/0022-1759(88)90240-2. [DOI] [PubMed] [Google Scholar]
  19. Gamble J. R., Vadas M. A. Endothelial cell adhesiveness for human T lymphocytes is inhibited by transforming growth factor-beta 1. J Immunol. 1991 Feb 15;146(4):1149–1154. [PubMed] [Google Scholar]
  20. Gimbrone M. A., Jr Culture of vascular endothelium. Prog Hemost Thromb. 1976;3:1–28. [PubMed] [Google Scholar]
  21. Hodis H. N., Mack W. J., LaBree L., Cashin-Hemphill L., Sevanian A., Johnson R., Azen S. P. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA. 1995 Jun 21;273(23):1849–1854. [PubMed] [Google Scholar]
  22. Hurme M. Modulation of interleukin-1 beta production by cyclic AMP in human monocytes. FEBS Lett. 1990 Apr 9;263(1):35–37. doi: 10.1016/0014-5793(90)80699-j. [DOI] [PubMed] [Google Scholar]
  23. Jialal I., Fuller C. J., Huet B. A. The effect of alpha-tocopherol supplementation on LDL oxidation. A dose-response study. Arterioscler Thromb Vasc Biol. 1995 Feb;15(2):190–198. doi: 10.1161/01.atv.15.2.190. [DOI] [PubMed] [Google Scholar]
  24. Jialal I., Grundy S. M. Effect of dietary supplementation with alpha-tocopherol on the oxidative modification of low density lipoprotein. J Lipid Res. 1992 Jun;33(6):899–906. [PubMed] [Google Scholar]
  25. Jialal I., Grundy S. M. Preservation of the endogenous antioxidants in low density lipoprotein by ascorbate but not probucol during oxidative modification. J Clin Invest. 1991 Feb;87(2):597–601. doi: 10.1172/JCI115035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Johannsson A., Ellis D. H., Bates D. L., Plumb A. M., Stanley C. J. Enzyme amplification for immunoassays. Detection limit of one hundredth of an attomole. J Immunol Methods. 1986 Feb 27;87(1):7–11. doi: 10.1016/0022-1759(86)90337-6. [DOI] [PubMed] [Google Scholar]
  27. Kasama T., Kobayashi K., Fukushima T., Tabata M., Ohno I., Negishi M., Ide H., Takahashi T., Niwa Y. Production of interleukin 1-like factor from human peripheral blood monocytes and polymorphonuclear leukocytes by superoxide anion: the role of interleukin 1 and reactive oxygen species in inflamed sites. Clin Immunol Immunopathol. 1989 Dec;53(3):439–448. doi: 10.1016/0090-1229(89)90006-8. [DOI] [PubMed] [Google Scholar]
  28. Kobayashi E., Nakano H., Morimoto M., Tamaoki T. Calphostin C (UCN-1028C), a novel microbial compound, is a highly potent and specific inhibitor of protein kinase C. Biochem Biophys Res Commun. 1989 Mar 15;159(2):548–553. doi: 10.1016/0006-291x(89)90028-4. [DOI] [PubMed] [Google Scholar]
  29. Krakauer T. A sensitive ELISA for measuring the adhesion of leukocytic cells to human endothelial cells. J Immunol Methods. 1994 Dec 28;177(1-2):207–213. doi: 10.1016/0022-1759(94)90158-9. [DOI] [PubMed] [Google Scholar]
  30. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  31. Leake D. S., Rankin S. M. The oxidative modification of low-density lipoproteins by macrophages. Biochem J. 1990 Sep 15;270(3):741–748. doi: 10.1042/bj2700741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Li Q., Cathcart M. K. Protein kinase C activity is required for lipid oxidation of low density lipoprotein by activated human monocytes. J Biol Chem. 1994 Jul 1;269(26):17508–17515. [PubMed] [Google Scholar]
  33. Libby P., Hansson G. K. Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Invest. 1991 Jan;64(1):5–15. [PubMed] [Google Scholar]
  34. Lipton B. A., Parthasarathy S., Ord V. A., Clinton S. K., Libby P., Rosenfeld M. E. Components of the protein fraction of oxidized low density lipoprotein stimulate interleukin-1 alpha production by rabbit arterial macrophage-derived foam cells. J Lipid Res. 1995 Oct;36(10):2232–2242. [PubMed] [Google Scholar]
  35. Manson J. E., Gaziano J. M., Jonas M. A., Hennekens C. H. Antioxidants and cardiovascular disease: a review. J Am Coll Nutr. 1993 Aug;12(4):426–432. doi: 10.1080/07315724.1993.10718332. [DOI] [PubMed] [Google Scholar]
  36. Marchant C. E., Law N. S., van der Veen C., Hardwick S. J., Carpenter K. L., Mitchinson M. J. Oxidized low-density lipoprotein is cytotoxic to human monocyte-macrophages: protection with lipophilic antioxidants. FEBS Lett. 1995 Jan 23;358(2):175–178. doi: 10.1016/0014-5793(94)01393-f. [DOI] [PubMed] [Google Scholar]
  37. Marui N., Offermann M. K., Swerlick R., Kunsch C., Rosen C. A., Ahmad M., Alexander R. W., Medford R. M. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest. 1993 Oct;92(4):1866–1874. doi: 10.1172/JCI116778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. McCord J. M., Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969 Nov 25;244(22):6049–6055. [PubMed] [Google Scholar]
  39. Nishizuka Y. Studies and perspectives of protein kinase C. Science. 1986 Jul 18;233(4761):305–312. doi: 10.1126/science.3014651. [DOI] [PubMed] [Google Scholar]
  40. Ozaki Y., Ohashi T., Kume S. Potentiation of neutrophil function by recombinant DNA-produced interleukin 1a. J Leukoc Biol. 1987 Dec;42(6):621–627. doi: 10.1002/jlb.42.6.621. [DOI] [PubMed] [Google Scholar]
  41. Ozer N. K., Palozza P., Boscoboinik D., Azzi A. d-alpha-Tocopherol inhibits low density lipoprotein induced proliferation and protein kinase C activity in vascular smooth muscle cells. FEBS Lett. 1993 May 17;322(3):307–310. doi: 10.1016/0014-5793(93)81592-n. [DOI] [PubMed] [Google Scholar]
  42. Ozer N. K., Palozza P., Boscoboinik D., Azzi A. d-alpha-Tocopherol inhibits low density lipoprotein induced proliferation and protein kinase C activity in vascular smooth muscle cells. FEBS Lett. 1993 May 17;322(3):307–310. doi: 10.1016/0014-5793(93)81592-n. [DOI] [PubMed] [Google Scholar]
  43. Pawlowski N. A., Abraham E. L., Pontier S., Scott W. A., Cohn Z. A. Human monocyte-endothelial cell interaction in vitro. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8208–8212. doi: 10.1073/pnas.82.23.8208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Raetz C. R., Ulevitch R. J., Wright S. D., Sibley C. H., Ding A., Nathan C. F. Gram-negative endotoxin: an extraordinary lipid with profound effects on eukaryotic signal transduction. FASEB J. 1991 Sep;5(12):2652–2660. doi: 10.1096/fasebj.5.12.1916089. [DOI] [PubMed] [Google Scholar]
  45. Raines E. W., Dower S. K., Ross R. Interleukin-1 mitogenic activity for fibroblasts and smooth muscle cells is due to PDGF-AA. Science. 1989 Jan 20;243(4889):393–396. doi: 10.1126/science.2783498. [DOI] [PubMed] [Google Scholar]
  46. Reaven P. D., Khouw A., Beltz W. F., Parthasarathy S., Witztum J. L. Effect of dietary antioxidant combinations in humans. Protection of LDL by vitamin E but not by beta-carotene. Arterioscler Thromb. 1993 Apr;13(4):590–600. doi: 10.1161/01.atv.13.4.590. [DOI] [PubMed] [Google Scholar]
  47. Reddanna P., Whelan J., Burgess J. R., Eskew M. L., Hildenbrandt G., Zarkower A., Scholz R. W., Reddy C. C. The role of vitamin E and selenium on arachidonic acid oxidation by way of the 5-lipoxygenase pathway. Ann N Y Acad Sci. 1989;570:136–145. doi: 10.1111/j.1749-6632.1989.tb14914.x. [DOI] [PubMed] [Google Scholar]
  48. Riemersma R. A., Wood D. A., Macintyre C. C., Elton R. A., Gey K. F., Oliver M. F. Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene. Lancet. 1991 Jan 5;337(8732):1–5. doi: 10.1016/0140-6736(91)93327-6. [DOI] [PubMed] [Google Scholar]
  49. 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 May 20;328(20):1450–1456. doi: 10.1056/NEJM199305203282004. [DOI] [PubMed] [Google Scholar]
  50. Rola-Pleszczynski M., Lemaire I. Leukotrienes augment interleukin 1 production by human monocytes. J Immunol. 1985 Dec;135(6):3958–3961. [PubMed] [Google Scholar]
  51. Ross R. Cell biology of atherosclerosis. Annu Rev Physiol. 1995;57:791–804. doi: 10.1146/annurev.ph.57.030195.004043. [DOI] [PubMed] [Google Scholar]
  52. Salonen J. T., Salonen R., Seppänen K., Rinta-Kiikka S., Kuukka M., Korpela H., Alfthan G., Kantola M., Schalch W. Effects of antioxidant supplementation on platelet function: a randomized pair-matched, placebo-controlled, double-blind trial in men with low antioxidant status. Am J Clin Nutr. 1991 May;53(5):1222–1229. doi: 10.1093/ajcn/53.5.1222. [DOI] [PubMed] [Google Scholar]
  53. Scaccini C., Jialal I. LDL modification by activated polymorphonuclear leukocytes: a cellular model of mild oxidative stress. Free Radic Biol Med. 1994 Jan;16(1):49–55. doi: 10.1016/0891-5849(94)90242-9. [DOI] [PubMed] [Google Scholar]
  54. Schmuck A., Fuller C. J., Devaraj S., Jialal I. Effect of aging on susceptibility of low-density lipoproteins to oxidation. Clin Chem. 1995 Nov;41(11):1628–1632. [PubMed] [Google Scholar]
  55. Shapira L., Takashiba S., Champagne C., Amar S., Van Dyke T. E. Involvement of protein kinase C and protein tyrosine kinase in lipopolysaccharide-induced TNF-alpha and IL-1 beta production by human monocytes. J Immunol. 1994 Aug 15;153(4):1818–1824. [PubMed] [Google Scholar]
  56. Stampfer M. J., Hennekens C. H., Manson J. E., Colditz G. A., Rosner B., Willett W. C. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993 May 20;328(20):1444–1449. doi: 10.1056/NEJM199305203282003. [DOI] [PubMed] [Google Scholar]
  57. Steinberg D., Parthasarathy S., Carew T. E., Khoo J. C., Witztum J. L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989 Apr 6;320(14):915–924. doi: 10.1056/NEJM198904063201407. [DOI] [PubMed] [Google Scholar]
  58. Steiner M. Effect of alpha-tocopherol administration on platelet function in man. Thromb Haemost. 1983 Apr 28;49(2):73–77. [PubMed] [Google Scholar]
  59. Stewart-Lee A. L., Forster L. A., Nourooz-Zadeh J., Ferns G. A., Anggård E. E. Vitamin E protects against impairment of endothelium-mediated relaxations in cholesterol-fed rabbits. Arterioscler Thromb. 1994 Mar;14(3):494–499. doi: 10.1161/01.atv.14.3.494. [DOI] [PubMed] [Google Scholar]
  60. Suzuki Y. J., Packer L. Inhibition of NF-kappa B activation by vitamin E derivatives. Biochem Biophys Res Commun. 1993 May 28;193(1):277–283. doi: 10.1006/bbrc.1993.1620. [DOI] [PubMed] [Google Scholar]
  61. Thomas C. E., Jackson R. L., Ohlweiler D. F., Ku G. Multiple lipid oxidation products in low density lipoproteins induce interleukin-1 beta release from human blood mononuclear cells. J Lipid Res. 1994 Mar;35(3):417–427. [PubMed] [Google Scholar]
  62. Wang A. M., Doyle M. V., Mark D. F. Quantitation of mRNA by the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9717–9721. doi: 10.1073/pnas.86.24.9717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Wang X., Feuerstein G. Z., Gu J. L., Lysko P. G., Yue T. L. Interleukin-1 beta induces expression of adhesion molecules in human vascular smooth muscle cells and enhances adhesion of leukocytes to smooth muscle cells. Atherosclerosis. 1995 May;115(1):89–98. doi: 10.1016/0021-9150(94)05503-b. [DOI] [PubMed] [Google Scholar]
  64. Witztum J. L., Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991 Dec;88(6):1785–1792. doi: 10.1172/JCI115499. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES