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Cytokines in Collagen Disease–Related Atherogenesis - Dr. Shovman, et al reply To the Editor: We thank Dr. Pruzanski and coworkers for their interest in our editorial1 and welcome their comments. We agree that the group of secretory phospholipases A2 (sPLA2) and especially sPLA2 IIA are involved in the pathogenesis of atherosclerosis through their proinflammatory and proatherogenic effects. Recently several new studies provided evidence that the protective function of sPLA2 IIA in inflammation is also indicated. In particular, the efficient bactericidal properties of sPLA2 IIA resulting in decreased persistence of microbial pathogens in the vessel wall have been reported2-4. It is presumed that the ability of sPLA2 IIA to attack Staphylococcus aureus and other Gram-positive bacteria lies primarily in the enzyme, in the binding to the bacterial cell wall, the penetration of the wall, and the hydrolytic attack on the phospholipids of the bacterial cell membranes2,3. The protective effect of sPLA2 IIA against Gram-positive and Gram-negative bacteria was verified also in vivo through investigations of sPLA2 IIA-transgenic mice. The transgenic mice showed a significantly higher resistance to Staphylococcus aureus compared with the control animals4. Along with antibacterial characteristics, the antithrombotic properties of sPLA2 IIA have been described and associated with the inhibition of thrombin synthesis, decreasing the probability of thrombus formation5. Moreover, it was established that sPLA2 IIA may be responsible for enhanced clearance of oxidatively modified lipoproteins during inflammation via the liver and adrenals6-8. Recently, the antiinflammatory properties of sPLA2 IIA were established in an experimental model of carrageenin-induced pleurisy in rats9. The extent to which an expression of sPLA2 IIA has pathogenic or protective functions with respect to atherosclerosis depends possibly on whether expression of the enzyme as the consequence of an inflammatory reaction is induced locally in the vessel wall or systemically as the result of an acute-phase reaction10. Thus, local sPLA2 IIA expression in the vessel wall may be connected with several pathogenic effects, and generally through increased phospholipolysis of oxidatively modified lipoproteins by sPLA2 IIA, resulting in cellular lipid accumulation and foam cell formation10. On the other hand, the local expression of sPLA2 may have a protective effect associated with bactericidal activity and inhibition of thrombin synthesis. Systemic expression of sPLA2 IIA may engender the protective effect through removal of oxidatively modified lipoproteins from the bloodstream via the liver and to a lesser extent via the adrenals6-8. The insightful discussion by Pruzanski, et al is timely and highly relevant from the scientific and clinical points of view, and additional investigations regarding the role of the sPLA2 group in the pathogenesis of atherosclerosis are required. ORA SHOVMAN, MD; BORIS GILBURD, MD, Center for Autoimmune Diseases and Department of Medicine B, Sheba Medical Center; YEHUDA SHOENFELD, MD, FRCP, Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv University, Center for Autoimmune Diseases and Department of Medicine B, Sheba Medical Center and Sackler Faculty of Medicine, Tel-Aviv University. Address reprint requests to Prof. Y. Shoenfeld, Sheba Medical Center, Department of Medicine B, Tel Hashomer, Ramat-Gan, 52621, Israel. E-mail: shoenfel@post.tau.ac.il REFERENCES 1. Shovman O, Gilburd B, Shoenfeld Y. The role of inflammatory cytokines in the pathogenesis of systemic lupus erythematosus-related atherosclerosis: a novel target for treatment? [editorial]. J Rheumatol 2006;33:445-7. [MEDLINE] 2. Buckland AG, Wilton DC. The antibacterial properties of secreted phospholipases A2. Biochim Biophys Acta 2000;1488:71-82. [MEDLINE] 3. Foreman-Wykert AK, Weinrauch Y, Elsbach P, Weiss J. Cell-wall determinants of the bactericidal action of group IIA phospholipase A2 against Gram-positive bacteria. J Clin Invest 1999;103:715-21. [MEDLINE] 4. Laine VJ, Grass DS, Nevalainen TJ. Protection by group II phospholipase A2 against Staphylococcus aureus. J Immunol 1999;162:7402-8. [MEDLINE] 5. Mounier CM, Hackeng TM, Schaeffer F, Faure G, Bon C, Griffin JH. Inhibition of prothrombinase by human secretory phospholipase A2 involves binding to factor Xa. J Biol Chem 1998;273:23764-72. [MEDLINE] 6. Eckey R, Menschikowski M, Lattke P, et al. Increased hepatic cholesterol accumulation in transgenic mice overexpressing human secretory phospholipase A2 group IIA. Inflammation 2004;28:59-65. [MEDLINE] 7. Labeque R, Mullon CJ, Ferreira JP, et al. Enzymatic modification of plasma low density lipoproteins in rabbits: a potential treatment for hypercholesterolemia. Proc Natl Acad Sci USA 1993;90:3476-80. [MEDLINE] 8. Tietge UJ, Maugeais C, Cain W, Rader DJ. Acute inflammation increases selective uptake of HDL cholesteryl esters into adrenals of mice overexpressing human sPLA2. Am J Physiol Endocrinol Metab 2003;285:403-11. [MEDLINE] 9. Gilroy DW, Newson J, Sawmynaden P, Willoughby DA, Croxtall JD. A novel role for phospholipase A2 isoforms in the checkpoint control of acute inflammation. FASEB J 2004;18:489-98. [MEDLINE] 10. Menschikowski M, Hagelgans A, Siegert G. Secretory phospholipase A2 of group IIA: is it an offensive or a defensive player during atherosclerosis and other inflammatory diseases? Prostaglandins Other Lipid Mediat 2006;79:1-33. [MEDLINE]
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