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Thematic review series: The Immune System and Atherogenesis. Cytokine regulation of macrophage functions in atherogenesis

2005; Elsevier BV; Volume: 46; Issue: 9 Linguagem: Inglês

10.1194/jlr.r500009-jlr200

1539-7262

Alan Daugherty, Nancy R. Webb, Debra L. Rateri, Victoria King,

Galectins and Cancer Biology

This review will focus on the role of cytokines in the behavior of macrophages, a prominent cell type of atherosclerotic lesions. Once these macrophages have immigrated into the vessel wall, they propagate the development of atherosclerosis by modifying lipoproteins, accumulating intracellular lipids, remodeling the extracellular environment, and promoting local coagulation. The numerous cytokines that have been detected in atherosclerosis, combined with the expression of large numbers of cytokine receptors on macrophages, are consistent with this axis being an important contributor to lesion development. Given the vast literature on cytokine-macrophage interactions, this review will be selective, with an emphasis on the major cytokines that have been detected in atherosclerotic lesions and their effects on properties that are relevant to lesion formation and maturation. There will be an emphasis on the role of cytokines in regulating lipid metabolism by macrophages.We will provide an overview of the major findings in cell culture and then put these in the context of in vivo studies. This review will focus on the role of cytokines in the behavior of macrophages, a prominent cell type of atherosclerotic lesions. Once these macrophages have immigrated into the vessel wall, they propagate the development of atherosclerosis by modifying lipoproteins, accumulating intracellular lipids, remodeling the extracellular environment, and promoting local coagulation. The numerous cytokines that have been detected in atherosclerosis, combined with the expression of large numbers of cytokine receptors on macrophages, are consistent with this axis being an important contributor to lesion development. Given the vast literature on cytokine-macrophage interactions, this review will be selective, with an emphasis on the major cytokines that have been detected in atherosclerotic lesions and their effects on properties that are relevant to lesion formation and maturation. There will be an emphasis on the role of cytokines in regulating lipid metabolism by macrophages. We will provide an overview of the major findings in cell culture and then put these in the context of in vivo studies. As noted in Getz's overview (1Getz G.S. Thematic review series: the immune system and atherogenesis. Immune function in atherogenesis.J. Lipid Res. 2005; 46: 1-10Google Scholar), lesions contain large numbers of cytokines that can be derived from several cell types. These cytokines may affect the function of many cell types in atherogenesis. The effects of cytokines on endothelial and smooth muscle cells are discussed in Raines and Ferri's contribution to this series (2Raines E.W. Ferri N. Cytokines affecting endothelial and smooth muscle cells in vascular diseases.J. Lipid Res. 2005; 46: 829-838Google Scholar). The purpose of this review is to focus on the effects of cytokines on macrophages in the evolution of atherosclerotic lesions. This is a vast literature that has necessitated some selectivity in the areas that can be covered. Given the subject area of this journal, we have elected to focus particular attention on the effect of cytokines on lipid metabolism in macrophages. Macrophages are hypothesized to be attracted to the subendothelial space to remove noxious materials deposited at atherosclerosis-prone regions of arteries. The precise chemical identity of the substance that attracts macrophages has not been unequivocally defined, although many candidate molecules are components of modified lipoproteins (3Steinberg D. Low density lipoprotein oxidation and its pathobiological significance.J. Biol. Chem. 1997; 272: 20963-20966Google Scholar, 4Shishehbor M.H. Hazen S.L. Inflammatory and oxidative markers in atherosclerosis: relationship to outcome.Curr. Atheroscler. Rep. 2004; 6: 243-250Google Scholar). However, the function of infiltrating cells becomes subverted and leads to their retention within the subendothelial space. In this region, it is proposed that macrophages modify adjacent lipoproteins while also providing major mechanisms of removal for modified materials from the extracellular environment. The combination of lipoprotein modification and uptake leads to macrophages becoming engorged with lipids and resulting in a morphology that is given the descriptive name of "foam cells." Lipid engorgement causes pronounced cellular hypertrophy, with the cell diameter being >10 times that of the originating monocyte. Probably as a result of the immense size increase, lipid-laden macrophages are chronically entrapped in the subendothelial space. Trapped macrophages can then invoke processes that perpetuate the continual recruitment of monocytes, leading to an expanded lesion volume. In addition, the subendothelial macrophages can influence the behavior of neighboring cell types within atherosclerotic lesions. This includes the well-characterized interaction of macrophages and T-lymphocytes (5Hansson G.K. Immune mechanisms in atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1876-1890Google Scholar). During late stages of atherosclerosis development, exposure of macrophage-rich areas of lesions provides a nidus for thrombus attachment that is thought to account for a high proportion of the catastrophic consequences of atherosclerosis. At each stage of lesion development described above, cytokine interactions with macrophages have the potential to be major determinants of the mechanism and magnitude of the response. The macrophage is probably the most phenotypically diverse cell type in the body (6Gordon S. The macrophage.Bioessays. 1995; 17: 977-986Google Scholar). From the common origin of monocytes, macrophages take on different characteristics that are presumably determined by the local milieu of the tissue into which they migrate. Although dissimilar between tissues, macrophages within a specific tissue have less heterogeneity. However, this is not the case in atherosclerosis, in which there are considerable variances in the structures of macrophages that may reflect a divergent array of functional abilities. Many contributions to our knowledge of cytokine effects on macrophage biology in atherosclerosis are derived from studies of cultured cells. The classic system in this area of investigation is primary cultures of macrophages derived from peritoneal lavage of mice (7Goldstein J.L. Ho Y.K. Brown M.S. Cholesteryl ester accumulation in macrophages resulting from receptor-mediated uptake and degradation of hypercholesterolemic canine beta-very low density lipoproteins.J. Biol. Chem. 1980; 255: 1839-1848Google Scholar). Many studies have also used macrophages derived from human monocytes. In addition to primary cells, there are also a wide variety of macrophage-like cell lines. Some of the most commonly used cell lines include the human-derived THP-1 (8Du B.H. Fu C.Z. Kent K.C. Bush H. Schulick A.H. Kreiger K. Collins T. McCaffrey T.A. Elevated Egr-1 in human atherosclerotic cells transcriptionally represses the transforming growth factor-beta type II receptor.J. Biol. Chem. 2000; 275: 39039-39047Google Scholar) and the mouse lines J774 and P388D1 (9Okwu A.K. Xu X.X. Shiratori Y. Tabas I. Regulation of the threshold for lipoprotein-induced acyl-CoA:cholesterol O-acyltransferase stimulation in macrophages by cellular sphingomyelin content.J. Lipid Res. 1994; 35: 644-655Google Scholar, 10Daugherty A. Whitman S.C. Block A.E. Rateri D.L. Polymorphism of class A scavenger receptors in C57BL/6 mice.J. Lipid Res. 2000; 41: 1568-1577Google Scholar). Although these cultured cells have some macrophage characteristics, the extent to which they mimic the cells present in atherosclerosis remains an open question. The assessment of similarities and differences of macrophages in culture versus those within atherosclerotic lesions is hampered by the fluid nature of macrophage phenotypes and the dearth of reagents to specifically define these phenotypes. The combination of this extensive heterogeneity and the imprecision of phenotyping may contribute to the conflicting reports of the effects of cytokines on some properties of macrophage biology that are described in this review. An early event in the development of atherosclerotic lesions is the subendothelial deposition of lipoproteins (11Kruth H.S. Subendothelial accumulation of unesterified cholesterol. An early event in atherosclerotic lesion development.Atherosclerosis. 1985; 57: 337-341Google Scholar, 12Frank J.S. Fogelman A.M. Ultrastructure of the intima in WHHL and cholesterol-fed rabbit aortas prepared by ultra-rapid freezing and freeze etching.J. Lipid Res. 1989; 30: 967-978Google Scholar). The presence of lipoproteins in the subendothelial space leads to substances that promote both chemotaxis and lipid accumulation in macrophages. Several modifications can promote both of these properties (3Steinberg D. Low density lipoprotein oxidation and its pathobiological significance.J. Biol. Chem. 1997; 272: 20963-20966Google Scholar, 13Quinn M.T. Parthasarathy S. Fong L.G. Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis.Proc. Natl. Acad. Sci. USA. 1987; 84: 2995-2998Google Scholar). In the early phases of lesion formation, lipoprotein modification occurs, presumably mostly mediated by endothelial mechanisms (14Williams K.J. Tabas I. The response-to-retention hypothesis of early atherogenesis.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 551-561Google Scholar). However, once atherogenesis has been initiated, macrophages may become a major cell type responsible for lipoprotein modification within lesions. There have been several pathways proposed for lipoprotein modification that are regulated by interactions of cytokines with macrophages. Much of the focus of the study of these modifications has been on oxidative mechanisms. Oxidation of LDL by cultured mouse peritoneal macrophages, as defined by the content of thiobarbituric acid-reacting substances, is decreased by incubating cells with interferon (IFN)-γ (15Fong L.G. Albert T.S.E. Hom S.E. Inhibition of the macrophage-induced oxidation of low density lipoprotein by interferon-gamma.J. Lipid Res. 1994; 35: 893-904Google Scholar). One potential mechanism of IFN-γ-induced reduction of LDL oxidation is an acceleration of extracellular tryptophan degradation (16Christen S. Thomas S.R. Garner B. Stocker R. Inhibition by interferon-gamma of human mononuclear cell-mediated low density lipoprotein oxidation—participation of tryptophan metabolism along the kynurenine pathway.J. Clin. Invest. 1994; 93: 2149-2158Google Scholar). Several reports have demonstrated a role of IFN-γ via a lipoxygenase pathway that is also thought to involve oxidation (17Sun D.X. Funk C.D. Disruption of 12/15-lipoxygenase expression in peritoneal macrophages—enhanced utilization of the 5-lipoxygenase pathway and diminished oxidation of low density lipoprotein.J. Biol. Chem. 1996; 271: 24055-24062Google Scholar). Lipoxygenase, specifically the 15-isoenzyme, is expressed in lesional macrophages and colocalizes with immunologically defined oxidative epitopes of lipoproteins (18Ylä-Herttuala S. Rosenfeld M.E. Parthasarathy S. Glass C.K. Sigal E. Witztum J.L. Steinberg D. Colocalization of 15-lipoxygenase messenger RNA and protein with epitopes of oxidized low density lipoprotein in macrophage-rich areas of atherosclerotic lesions.Proc. Natl. Acad. Sci. USA. 1990; 87: 6959-6963Google Scholar, 19Ylä-Herttuala S. Rosenfeld M.E. Parthasarathy S. Sigal E. Sarkioja T. Witztum J.L. Steinberg D. Gene expression in macrophage-rich human atherosclerotic lesions—15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts.J. Clin. Invest. 1991; 87: 1146-1152Google Scholar). Expression of the enzyme in macrophages has been shown to promote atherosclerosis and lipoprotein oxidation (20Sendobry S.M. Cornicelli J.A. Welch K. Bocan T. Tait B. Trivedi B.K. Colbry N. Dyer R.D. Feinmark S.J. Daugherty A. Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties.Br. J. Pharmacol. 1997; 120: 1199-1206Google Scholar, 21Cyrus T. Witztum J.L. Rader D.J. Tangirala R. Fazio S. Linton M.F. Funk C.D. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice.J. Clin. Invest. 1999; 103: 1597-1604Google Scholar, 22Zhao L. Cuff C.A. Moss E. Wille U. Cyrus T. Klein E.A. Pratico D. Rader D.J. Hunter C.A. Pure E. et al.Selective interleukin-12 synthesis defect in 12/15-lipoxygenase-deficient macrophages associated with reduced atherosclerosis in a mouse model of familial hypercholesterolemia.J. Biol. Chem. 2002; 277: 35350-35356Google Scholar), although there are contrary data (23Shen J.H. Herderick E. Cornhill J.F. Zsigmond E. Kim H.S. Kuhn H. Guevara N.V. Chan L. Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development.J. Clin. Invest. 1996; 98: 2201-2208Google Scholar, 24Belkner J. Chaitidis P. Stender H. Gerth C. Kuban R.J. Yoshimoto T. Kuhn H. Expression of 12/15-lipoxygenase attenuates intracellular lipid deposition during in vitro foam cell formation.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 797-802Google Scholar). 15-Lipoxygenase is not expressed in cultured human monocytes, but its expression is profoundly stimulated by incubation with interleukin (IL)-4 or IL-13 (25Conrad D.J. Kuhn H. Mulkins M. Highland E. Sigal E. Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase.Proc. Natl. Acad. Sci. USA. 1992; 89: 217-221Google Scholar, 26Nassar G.M. Morrow J.D. Roberts L.J. Lakkis F.G. Badr K.F. Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes.J. Biol. Chem. 1994; 269: 27631-27634Google Scholar). The stimulation of lipoxygenase expression in these cells is ablated by coincubation with IFN-γ (25Conrad D.J. Kuhn H. Mulkins M. Highland E. Sigal E. Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase.Proc. Natl. Acad. Sci. USA. 1992; 89: 217-221Google Scholar). However, incubation of IFN-γ with mouse peritoneal macrophages, which contain abundant lipoxygenase activity on isolation, does not influence lipoxygenase protein abundance or activity (27Cornicelli J.A. Butteiger D. Rateri D.L. Welch K. Daugherty A. Interleukin-4 augments acetylated LDL induced cholesterol esterification in macrophages.J. Lipid Res. 2000; 41: 376-383Google Scholar). Therefore, the effect of IFN-γ appears to be via a mechanism that inhibits the synthesis of the lipoxygenase. The contribution of these cytokines to lipoxygenase regulation in vivo is unclear, because mice deficient in IL-4 do not have reduced expression of lipoxygenase (27Cornicelli J.A. Butteiger D. Rateri D.L. Welch K. Daugherty A. Interleukin-4 augments acetylated LDL induced cholesterol esterification in macrophages.J. Lipid Res. 2000; 41: 376-383Google Scholar). This may be attributable to the continued presence of IL-13 (26Nassar G.M. Morrow J.D. Roberts L.J. Lakkis F.G. Badr K.F. Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes.J. Biol. Chem. 1994; 269: 27631-27634Google Scholar). However, lipoxygenase expression is unexpectedly increased in total lymphocyte-deficient mice that are assumed to have low circulating concentrations of cytokines. Also, there is no effect of STAT-6 deficiency, which is a common pathway for the effects of both IL-4 and IL-13 (28Sendobry S.M. Cornicelli J.A. Welch K. Grusby M.J. Daugherty A. Absence of T lymphocyte-derived cytokines fails to diminish macrophage 12/15-lipoxygenase expression in vivo.J. Immunol. 1998; 161: 1477-1482Google Scholar). Myeloperoxidase is present in large amounts in monocytes and has been proposed as a major oxidative enzyme in atherosclerosis (29Daugherty A. Dunn J.L. Rateri D.L. Heinecke J.W. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions.J. Clin. Invest. 1994; 94: 437-444Google Scholar). The role of myeloperoxidase in the development of atherosclerosis has not been defined, although the protein and many oxidative products of its activity have been detected in lesions (29Daugherty A. Dunn J.L. Rateri D.L. Heinecke J.W. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions.J. Clin. Invest. 1994; 94: 437-444Google Scholar, 30Brennan M.L. Anderson M.M. Shih D.M. Qu X.D. Wang X. Mehta A.C. Lim L.L. Shi W. Hazen S.L. Jacob J.S. et al.Increased atherosclerosis in myeloperoxidase-deficient mice.J. Clin. Invest. 2001; 107: 419-440Google Scholar, 31Podrez E.A. Abu-Soud H.M. Hazen S.L. Myeloperoxidase-generated oxidants and atherosclerosis.Free Radic. Biol. Med. 2000; 28: 1717-1725Google Scholar, 32Heinecke J.W. Oxidative stress: new approaches to diagnosis and prognosis in atherosclerosis.Am. J. Cardiol. 2003; 91: 12A-16AGoogle Scholar). The cytokine regulation of myeloperoxidase in macrophages has been given limited attention. Granulocyte macrophage colony-stimulating factor (GM-CSF), but not monocyte colony-stimulating factor (M-CSF), increases the expression of myeloperoxidase in macrophages (33Sugiyama S. Okada Y. Sukhova G.K. Virmani R. Heinecke J.W. Libby P. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes.Am. J. Pathol. 2001; 158: 879-891Google Scholar). Lipoproteins can also be modified within lesions by nonoxidative processes. These include the effects of LPL expressed in macrophages of atherosclerotic lesions (34Ylä-Herttuala S. Lipton B.A. Rosenfeld M.E. Goldberg I.J. Steinberg D. Witztum J.L. Macrophages and smooth muscle cells express lipoprotein lipase in human and rabbit atherosclerotic lesions.Proc. Natl. Acad. Sci. USA. 1991; 88: 10143-10147Google Scholar). The absence of LPL in macrophages decreases atherosclerosis (35Babaev V.R. Fazio S. Gleaves L.A. Carter K.J. Semenkovich C.F. Linton M.F. Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in vivo.J. Clin. Invest. 1999; 103: 1697-1705Google Scholar, 36van Eck M. Zimmermann R. Groot P.H. Zechner R. van Berkel T.J. Role of macrophage-derived lipoprotein lipase in lipoprotein metabolism and atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2000; 20: E53-E62Google Scholar), whereas overexpression in this cell type increases lesion size (37Wilson K. Fry G.L. Chappell D.A. Sigmund C.D. Medh J.D. Macrophage-specific expression of human lipoprotein lipase accelerates atherosclerosis in transgenic apolipoprotein E knockout mice but not in C57BL/6 mice.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1809-1815Google Scholar). IFN-γ decreases the expression of LPL in human monocyte-derived macrophages from early to late stages of culture (38Jonasson L. Hansson G.K. Bondjers G. Noe L. Etienne J. Interferon-gamma inhibits lipoprotein lipase in human monocyte-derived macrophages.Biochim. Biophys. 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A critical role for the Sp1-binding sites in the transforming growth factor-beta-mediated inhibition of lipoprotein lipase gene expression in macrophages.Nucleic Acids Res. 2005; 33: 1423-1434Google Scholar), but it is upregulated by tumor necrosis factor (TNF)-α (43Renier G. Skamene E. DeSanctis J.B. Radzioch D. Induction of tumor necrosis factor alpha gene expression by lipoprotein lipase.J. Lipid Res. 1994; 35: 271-278Google Scholar). Thus, there is substantial evidence that cytokine regulation may be an important contributor to the atherogenic effects of macrophage-expressed LPL. Although LPL can modify specific lipoprotein fractions, it is possible that nonlipolytic properties of the protein are responsible for its effects in atherogenesis (44Williams K.J. Fless G.M. Petrie K.A. Snyder M.L. Brocia R.W. Swenson T.L. Mechanisms by which lipoprotein lipase alters cellular metabolism of lipoprotein(a), low density lipoprotein, and nascent lipoproteins—roles for low density lipoprotein receptors and heparan sulfate proteoglycans.J. Biol. Chem. 1992; 267: 13284-13292Google Scholar). One of the most prominent changes in macrophages after entry into the subendothelial space of developing atherosclerotic lesions is the engorgement of these cells with lipid. Intracellular lipid stores are initially formed with simple droplet morphology. With progressive lipid engorgement, there is the formation of intracellular complexes of cholesterol and phospholipid and cholesterol crystals (45Jerome W.G. Lewis J.C. Cellular dynamics in early atherosclerotic lesion progression in white carneau pigeons—spatial and temporal analysis of monocyte and smooth muscle invasion of the intima.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 654-664Google Scholar, 46Jerome W.G. Yancey P.G. The role of microscopy in understanding atherosclerotic lysosomal lipid metabolism.Microsc. Microanal. 2003; 9: 54-67Google Scholar). These complexes and crystals are frequently encased by an acid phosphatase-positive layer, consistent with entrapment in lysosomes or late endosomes. It is now recognized that many receptors are present on macrophages that bind a wide range of native and modified lipoproteins. Several major receptor types that recognize native lipoproteins may be regulated by cytokines in macrophages. LDL receptors have a clearly defined role in the cholesterol homeostasis of the whole body. Their role in macrophages has not been explored widely because of the assumption that they are downregulated in lipid-laden lesional macrophages. However, LDL receptor protein is detectable in experimental atherosclerotic lesions (47Boisvert W.A. Spangenberg J. Curtiss L.K. Role of leukocyte-specific LDL receptors on plasma lipoprotein cholesterol and atherosclerosis in mice.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 340-347Google Scholar, 48Herijgers N. Eck M. van Groot P.H.E. Hoogerbrugge P.M. van Berkel T.J.C. Low density lipoprotein receptor of macrophages facilitates atherosclerotic lesion formation in C57B1/6 mice.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1961-1967Google Scholar). Furthermore, macrophage LDL receptors influence atherogenesis under conditions of modest hyperlipidemia (48Herijgers N. Eck M. van Groot P.H.E. Hoogerbrugge P.M. van Berkel T.J.C. Low density lipoprotein receptor of macrophages facilitates atherosclerotic lesion formation in C57B1/6 mice.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1961-1967Google Scholar, 49Linton M.F. Babaev V.R. Gleaves L.A. Fazio S. A direct role for the macrophage low density lipoprotein receptor in atherosclerotic lesion formation.J. Biol. Chem. 1999; 274: 19204-19210Google Scholar). 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Expression of LDL receptors may also have implications on the mode of metabolism of the highly atherogenic lipoprotein fraction, β-VLDL, which may have characteristics similar to those of postprandial chylomicron lipoproteins (48Herijgers N. Eck M. van Groot P.H.E. Hoogerbrugge P.M. van Berkel T.J.C. Low density lipoprotein receptor of macrophages facilitates atherosclerotic lesion formation in C57B1/6 mice.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1961-1967Google Scholar, 49Linton M.F. Babaev V.R. Gleaves L.A. Fazio S. A direct role for the macrophage low density lipoprotein receptor in atherosclerotic lesion formation.J. Biol. Chem. 1999; 274: 19204-19210Google Scholar). In addition to LDL receptors, β-VLDL is also recognized by VLDL receptors. This receptor type is also expressed on macrophages and is downregulated by IFN-γ (52Kosaka S. Takahashi S. Masamura K. Kanehara H. Sakai J. Tohda G. Okada E. Oida K. Iwasaki T. 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LRP: a multifunctional scavenger and signaling receptor.J. Clin. Invest. 2001; 108: 779-784Google Scholar). Many of these ligands are responsible for regulating the extracellular proteolytic environment of macrophages (58Gonias S.L. Wu L. Salicioni A.M. Low density lipoprotein receptor-related protein: regulation of the plasma membrane proteome.Thromb. Haemost. 2004; 91: 1056-1064Google Scholar). Although there has been limited work on the cytokine regulation of native lipoprotein receptors, there has been considerable effort to study the cytokine regulation of receptors for modified lipoproteins. As discussed in the preceding section, there are several mechanisms of lipoprotein modification that can be regulated by cytokines. Many of these modifications involve some form of oxidative damage. The original receptor for modified lipoproteins was designated a "scavenger receptor" based on its ability to mediate the endocytosis of acetylated LDL (59Brown M.S. Basu S.K. Falck J.R. Ho Y.K. Goldstein J.L. The scavenger cell pathway for lipoprotein degradation: specificity of the binding site that mediates the uptake of negatively-charged LDL by macrophages.J. Supramol. Struct. 1980; 13: 67-81Google Scholar). There are now many proteins that have been designated as scavenger receptors that are broadly classified by gross structural characteristics in an alphabetic system (8Du B.H. Fu C.Z. Kent K.C. Bush H. Schulick A.H. Kreiger K. Collins T. McCaffrey T.A. Elevated Egr-1 in human atheroscleroti