Objective: We have previously demonstrated that Mediterranean glucose-6-phosphate dehydrogenase (G6PD)-deficient peripheral blood mononuclear cells (PBMC) respond to mitogenic stimuli with a reduced cholesterol synthesis and growth. In the present study, we have investigated the release of inflammatory molecules by PBMC following a mitogenic stimulus, as well as the transformation to foam cells of monocyte-derived macrophages from severely G6PD-deficient and normal subjects. Methods and Results: PBMC from G6PD-deficient subjects produced interleukin (IL)-1β and IL-6 to a lower extent compared with normal subjects. 5-Hydroxyeicosatetraenoic acid, a primary product of 5-lipoxygenase, was slightly decreased. Tumour necrosis factor-α and IL-1β secretion was significantly reduced in monocyte-derived macrophages. No difference was found in IL-10 secretion, whereas transforming growth factor-β was invariably found to be significantly higher in G6PD-deficient cells. In cells incubated with acetylated low-density lipoprotein, cholesterol esterification and its storage in lipid droplets were lower than in normal G6PD cells. Conclusions: We conclude that by reducing the secretion of inflammatory molecules by PBMC and increasing the secretion of transforming growth factor-β and the capability of monocyte-derived macrophages to accumulate lipid droplets and convert into foam cells, G6PD deficiency may confer a partial protection against atherosclerosis leading to the reduced risk of cardiovascular diseases reported in G6PD-deficient subjects.

Keywords:
Glucose-6-phosphate dehydrogenase deficiency, Atherosclerosis, Blood cells, Inflammatory cytokines
1.
Luzzatto L, Metha AB: Glucose-6-phosphate dehydrogenase deficiency; in Senver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic Basis of Inherited Disease. London, McGraw-Hill, 1989, vol 2, 2237–2265.
2.
Vulliamy T, Mason P, Luzzatto L: The molecular basis of glucose-6-phosphate dehydrogenase deficiency. Trends Genet 1992;8:138–143.
3.
Kletzien RF, Harris PKV, Foellmi L: Glucose-6-phosphate dehydrogenase: a ‘housekeeping’ enzyme subject to tissue-specific regulation by hormones, nutrients, and oxidant stress. FASEB J 1994;8:174–181.
4.
Cuthbert JA, Lipsky PE: Regulation of lymphocytes proliferation by cholesterol: the role of endogenous metabolism and low density lipoprotein receptors. Int J Tissue React 1987;9:447–457.
5.
Cuthbert JA, Lipsky PE: Mitogenic stimulation alters the regulation of LDL receptor gene expression in human lymphocytes. J Lipid Res 1990;31:2067–2078.
6.
Roitt IV, Brostoff J, Male DK: Immunology; in Roitt IV, Brostoff J, Male DK (eds): Immunology. Edinburg, Mosby, 2001.
7.
Batetta B, Pulisci D, Bonatesta RR, Sanna F, Piras S, Mulas MF, Spano O, Putzolu M, Broccia G, Dessì S: G6PD activity and gene expression in leukemic cells from G6PD deficient subjects. Cancer Lett 1999;140:53–58.
8.
Batetta B, Bonatesta RR, Sanna F, Putzolu M, Mulas MF, Collu M, Dessì S: Cell growth and cholesterol metabolism in human glucose-6-phosphate dehydrogenase deficient lymphomononuclear cells. Cell Prolif 2002;35:143–154.
9.
Ross R: The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801–809.
10.
Ross R: Mechanisms of disease: atherosclerosis – an inflammatory disease. N Engl J Med 1999;340:115–126.
11.
Libby P: Inflammation in atherosclerosis. Nature 2002;420:868–874.
12.
Spanbroek R, Gräbner R, Lötzer K, Hildner M, Urbach A, Ruhiling K, Moos MP, Kaiser B, Cohnert TU, Wahlers T, Zieske A, Plenz G, Robenek H, Salbach P, Kuhn H, Radmark O, Samuelsson B, Habenicht AJ: Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc Natl Acad Sci 2003;100:1238–1243.
13.
Mehrabian M, Allayee H, Wong J, Shi W, Wang XP, Shaposhnik Z, Funk CD, Lusis AJ: Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res 2002;91:120–126.
14.
Calandra S, Bertolini S, Pes GM, Deiana L, Tarugi P, Pisciotta L, Li Volti S, Maccarone C: β-Thalassemia is a modifying factor of the clinical expression hypercholesterolemia. Semin Vasc Med 2004;4:271–278.
15.
Betke K, Brewer GJ, Kirkman AN, Luzzatto L, Motulsky AG, Ramot B, Siniscalco M: Standardization of procedures for the study of glucose-6-phosphate dehydrogenase: report of WHO scientific group. WHO Tech Rep Ser 1967;366:1–53.
16.
Ho YK, Browns MS, Bilheimer DW, Goldstein JL: Regulation of low density lipoprotein receptor activity in freshly isolated human PBMC. J Clin Invest 1976;58:1465–1474.
17.
Van Den Eijnden MMED, van Noort JT, Hollaar L, van der Laarse A, Bertina RM: Cholesterol or triglyceride loading of human monocyte-derived macrophages by incubation with modified lipoproteins does not induce tissue factor expression. Arterioscler Thromb Vasc Biol 1999;19:384–392.
18.
Glock GE, McLean P: Further studies on the properties and assay of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase of rat liver. Biochem J 1953;55:400–408.
19.
Lowry OH, Rosebrough NJ, Farr JL, Randall RJ: Protein measurement with Folin phenol reagent. J Biol Chem 1951;193:265–275.
20.
Mantovani G, Macciò A, Esu S, Lai P, Santona MC, Massa E, Dessì D, Melis GB, Del Giacco GS: Lack of correlation between defective cell-mediated immunity and levels of secreted or circulating cytokines in a study of 90 cancer patients. Eur J Cancer 1997;33:602–607.
21.
Gantner F, Kupferschmidt R, Schudt C, Wendel A, Hatzelmann A: In vitro differentiation of human monocytes to macrophages: change of PDE profile and its relationship to suppression of tumour necrosis factor-α release by PDE inhibitors. Br J Pharmacol 1997;121:221–231.
22.
Folch J, Lees M, Sloane-Stanley GH: A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957;222:497–509.
23.
Melis MP, Angioni E, Carta G, Murru E, Scanu P, Spada S, Banni S: Characterization of conjugated linoleic acid and its metabolites by RP-HPLC with diode array detector. Eur J Lipid Sci Technol 2001;103:617–621.
24.
Angioni E, Lercker G, Frega NG, Carta G, Melis MP, Murru E, Spada S, Banni S: UV spectral properties of lipids as a tool for their identification. Eur J Lipid Sci Technol 2002;104:59–64.
25.
Libby P, Ross R: Cytokines and growth regulatory molecules; in Fuster V, Ross R, Topol EJ (eds): Atherosclerosis and Coronary Artery Diseases. Philadelphia, Lippincott-Raven, vol 1, 1996, p 585.
26.
Dessì S, Chiodino C, Batetta B, Fadda AM, Anchisi C, Pani P: Glucose-6-phosphate dehydrogenase, cholesterogenesis, and serum lipoproteins in liver regeneration after partial hepatectomy. Exp Mol Pathol 1986;44:169–176.
27.
Dessì S, Batetta B, Spano O, Pulisci D, Mulas MF, Muntoni S, Armeni M, Pani P: Serum lipoprotein pattern as modified in G6PD-deficient children induced by fava bean ingestion. Int J Exp Pathol 1992;73:157–160.
28.
Paglialunga F, Fico A, Iaccarino I, Notaro R, Luzzato L, Martini G, Filona S: G6PD is indispensable for erythropoiesis after the embryonic-adult hemoglobin switch. Blood 2004;104:3148–3152.
29.
Park J, Rho HK, Kim KH, Choe SS, Lee YS, Kim JB: Overexpression of glucose-6-phosphate dehydrogenase is associated with lipid dysregulation and insulin resistance in obesity. Mol Cell Biol 2005;25:5146–5147.
30.
Muntoni S, Batetta B, Dessì S, Muntoni S, Pani P: Serum lipoprotein profile in the Mediterranean variant of glucose-6-phosphate dehydrogenase deficiency. Eur J Epidemiol 1992;8:48–53.
31.
Liese AM, Siddiqi MQ, Siegel JH, Deitch EA, Spolarics Z: Attenuated monocyte IL-10 production in glucose-6-phosphate dehydrogenase-deficient trauma patients. Shock 2002;18:18–23.
32.
Wilmanki J, Siddiqi M, Deicht EA, Spolarics Z: Augmented IL-10 production and redox-dependent signaling pathways in glucose-6-phosphate dehydrogenase-deficient mouse peritoneal macrophages. J Leukoc Biol 2005;78:85–94.
33.
Mortdmuller B, Turrini F, Long H, Kremsner PG, Arese P: Neutrophils and monocytes from subjects with the Mediterranean G6PD variant: effect of Plasmodium falciparum hemozoin on G6PD activity, oxidative burst and cytokine production. Eur Cytokine Netw 1998;9:239–246.
34.
Rady PL, Matalon R, Grady J, Smith EM, Hudnall SD, Kellner LH, Nitowsky H, Tyring SK, Hughes TK: Comprehensive analysis of genetic polymorphism in the interleukin-10 promoter: implication for immune regulation in specific ethnic populations. Genet Test 2004;8:194–203.
35.
Upperman JS, Pillage G, Siddiqi MQ, Zeevi A, Kelly N, Ford HR, Kammerer C, Spolarics Z: Dominance of high-producing interleukin 6 and low-producing interleukin 10 and interferon-γ alleles in glucose-6-phosphate dehydrogenase-deficient trauma patients. Shock 2005;23:197–201.
36.
Kriegel MA, Li MO, Sanjabi S, Wan YY, Flavell RA: Transforming growth factor-β: recent advances on its role in immune tolerance. Curr Rheumathol Rep 2006;8:138– 144.
37.
Mallat Z, Tedgui A: The role of transforming growth factor-β in atherosclerosis: novel insight and future perspectives. Curr Opin Lipidol 2002;13:523–529.
38.
Griendling KK, Sorescu D, Ushio-Fukai M: NADPH oxidase: role in cardiovascular biology and disease. Circ Res 2000;86:494–501.
39.
Barry-Lane PA, Patterson C, van der Merwe M: p47phox is required for atherosclerotic lesion progression in ApoE–/– mice. J Clin Invest 2001;108:1513–1522.
40.
Matsui R, Xu S, Maitland KA, Hayes A, Leopold JA, Handy DE, Loscalzo J, Cohen RA: Glucose-6-phosphate dehydrogenase deficiency decreases the vascular response to angiotensin II. Circulation 2005;112:257–263.
41.
Matsui R, Xu S, Maitland KA, Mastroianni R, Leopold JA, Handy DE, Loscalzo J, Cohen RA: Glucose-6-phosphate dehydrogenase deficiency decreases vascular superoxide and atherosclerotic lesions in apolipoprotein E–/– mice. Arterioscler Thromb Vasc Biol 2006;26:910–916.
42.
Feo F, Pirisi L, Pascale R, Daino L, Frassetto S, Garcea R, Gaspa L: Modulatory effect of glucose-6-phosphate dehydrogenase deficiency on benzo(a)pyrene toxicity and transforming activity for in vitro-cultured human skin fibroblasts. Cancer Res 1984;44:3419–3425.
43.
Feo F, Ruggiu ME, Lenzerini L, Garcea R, Daino L, Frassetto S, Garcea R, Addis V, Gaspa L, Pascale R: Benzo(a)pyrene metabolism by lymphocytes from normal individuals and individuals carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase. Int J Cancer 1987;39:560–564.
44.
Deiana L, Ferrucci L, Pes GM, Carru C, Delitala G, Ganau A, Mariotti S, Nieddu A, Pettinato S, Putzu P, Franceschi C, Baggio G: AKEntAnnos. The Sardinian study of extreme longevity. Aging (Milano) 1999;11:142–149.
45.
Schwartz AG, Pashko LL: Dehydroepiandrosterone, glucose-6-phosphate dehydrogenase, and longevity. Ageing Res Rev 2004;3:171–187.
46.
Cocco P, Todde P, Fornera S, Manca MB, Manca P, Sias AR: Mortality in a cohort of men expressing the glucose-6-phosphate deficiency. Blood 1998;91:706–709.
© 2007 S. Karger AG, Basel
2007
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.