© 1997 American Heart Association, Inc.
Articles |
Platelet-Activating Factor and Oxidized LDL Induce Immune Activation by a Common Mechanism
From the Department of Medicine, Division of Rheumatology, Karolinska Hospital (J.F., Y.H.H., J.R.), and the Department of Physiological Chemistry, Karolinska Institute (L.S.-E.), Stockholm, Sweden.
Correspondence to Johan Frostegård, Department of Medicine, Division of Rheumatology, Karolinska Hospital, Karolinska Institute, S-17176 Stockholm, Sweden. E-mail johanf{at}rheum.ks.se
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Abstract |
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Abstract Platelet activating factor (PAF) is a phospholipid with proinflammatory and thrombogenic properties, which has been implicated in inflammatory disorders including vasculitis and asthma. PAF-like compounds are present in oxidized LDL (oxLDL), which has been detected in the atherosclerotic lesion, where it may activate monocytes, macrophages, and T cells. OxLDL may therefore both initiate and perpetuate inflammatory reactions in the artery wall. Herein we demonstrate that PAF has the capacity to induce enhanced interferon gamma (IFN-
) secretion in peripheral blood mononuclear leukocytes (PBMCs), as does oxLDL. Both oxLDL- and PAF-induced IFN- secretions were inhibited by a specific PAF-receptor antagonist, WEB 2170. PAF-like lipids in oxLDL could thus be responsible for oxLDL-induced activation of immune-competent cells. The effects of PAF and oxLDL were inhibited by antibodies to major histocompatibility complex class II and thus depend on accessory cells like monocytes. Both PAF and oxLDL induced tumor necrosis factor-
(TNF-) synthesis in peripheral blood. PAF-mediated TNF- production was inhibited by WEB 2170, whereas oxLDL-induced TNF- was only partially inhibited. These findings indicate that both PAF and oxLDL have the capacity to induce TNF-, which may increase atherogenesis due to its pleiotropic proinflammatory effects. Our findings suggest that the PAF receptor plays an important role in the inflammatory component of atherosclerosis.
Key Words: platelet-activating factor • atherosclerosis • oxidized LDL • tumor necrosis factor • interferon gamma
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Introduction |
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Platelet-activating factor is a lipid mediator that has been shown to exert a wide range of biological activities. PAF induces vascular inflammation and vasculitis in both humans1 and experimental animals.2 PAF has also been described as a potent thrombogenic compound with effects on platelets, endothelial cells, and leukocytes.3 PAF plays a regulatory role in inflammatory reactions and in the production of a range of inflammatory cytokines,3 but the effects on the immune system are complex, and PAF has been shown to both increase and decrease mitogen-induced T-cell activation.4 5 Interestingly, vascular changes similar to early atherosclerosis have been observed after treatment with PAF,6 and treatment with a PAF inhibitor decreased diet-induced atherosclerosis in rabbits.7 Available data thus indicate that PAF plays an important role in vascular inflammation.
PAF is synthesized by several cell types including platelets, polymorphonuclear cells, endothelial cells, and monocytes/macrophages. Proinflammatory cytokines, immune complexes, and free radicals may induce PAF synthesis.3 PAF is degraded by a specific enzyme, PAF acetylhydrolase, present in both LDL and HDL.8 It is rapidly degraded in the circulation and is therefore likely to exert its effects locally in inflammatory lesions.
Many of the macrophages in atherosclerotic inflammatory lesions take up large amounts of lipids, mainly derived from oxidized or other forms of modified LDL. They bind and internalize oxLDL by specific scavenger receptors and transform into foam cells.9 10 11 In vitro, oxLDL has been demonstrated to exert cytotoxic effects at higher concentrations.12 However, oxLDL at lower concentrations and minimally oxLDL at higher concentrations have proinflammatory properties, including enhancing the adhesiveness of endothelial cells and monocytes,13 14 stimulation of IL-1 secretion by monocytes, differentiation of monocytes into macrophages,15 and activation of T lymphocytes.16 17 18 We have recently demonstrated that oxLDL induces enhanced IFN- secretion in lymphocytes from healthy individuals.18 However, little is known about the mechanisms by which oxLDL exerts its proinflammatory effects.
Like oxLDL, PAF has the capacity to activate monocytes.19 PAF acts by way of specific PAF receptors belonging to the G protein–coupled receptor family.20 Both monocytes/macrophages and granulocytes express significant amounts of PAF receptors, in contrast to peripheral-blood lymphocytes, which lack these receptors.21 However, after activation, B and T cells also express PAF receptors.22
It has been reported that LDL contains PAF and/or PAF-like lipids23 and that during oxidation of LDL, PAF-like lipids may be produced.24 It is therefore plausible that oxLDL and PAF could exert their effects via the same mechanisms. In support of this hypothesis, recent data indicate that intravenous injection of a specific PAF-receptor antagonist, WEB 2170, in experimental animals inhibits oxLDL-induced adhesion of polynuclear leukocytes to the vascular endothelium.25 PAF acetylhydrolase, an enzyme that can also hydrolyze oxidized phospholipids, abolishes oxLDL-induced biological activities,26 indicating that PAF-like lipids play an important role in the oxLDL-mediated interactions between endothelium and leukocytes.
We report in this study that PAF and oxLDL activate immune-competent cells by a PAF-receptor–dependent mechanism. The possible implications of these findings are discussed.
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Methods |
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Cell Culture
PBMCs from healthy blood donors were isolated from buffy coats that were diluted in PBS at a ratio of 1:4, layered onto Ficoll-Hypaque (Pharmacia), and centrifuged for 20 minutes at 800g. Cells at the interface were washed twice in PBS and then counted and resuspended in RPMI-1640 medium supplemented with HEPES buffer, penicillin, and streptomycin and 10% fetal calf serum (complete medium) at a cell concentration of 1x106/mL. Cell viability was determined by trypan blue exclusion and exceeded 95% in all experiments.
Preparation of LDL and OxLDL
LDL was prepared and oxidized essentially as described.18 Briefly, venous blood from healthy donors was drawn after overnight fasting and plasma was recovered by centrifugation at 1400g for 20 minutes at 1°C. LDL was isolated from plasma in the density interval 1.025 to 1.050 kg/L by sequential preparative ultracentrifugation27 in a 50.3 Ti Beckman fixed angle rotor (Beckman L8-80 ultracentrifuge) for 20 hours. The total protein content of the LDL preparation was determined by the technique of Lowry et al.28
LDL was dialyzed in 0.02 mol/L phosphate/0.16 mol/L NaCl buffer, pH 7.4, for 15 hours at 4°C to remove EDTA. LDL was then oxidized by incubation of 0.2 mg/mL LDL in medium F-10 Ham containing 10 µmol/L CuSO4 overnight at 37°C. Exposure of native LDL to 10 µmol/L Cu2+ for 16 hours at 37°C resulted in a significant increase in the amount of thiobarbituric acid–reactive substances present in the LDL preparation and in an increased mobility during agarose gel electrophoresis (data not shown). Each preparation of oxLDL was used within 48 hours of the oxidation.
PAF, lyso-PAF, and LPS were obtained from Sigma Chemical Company. A specific PAF-receptor antagonist, WEB 2170, was a kind gift from Boehringer-Ingelheim, Ingelheim-am-Rhein, Germany.
Detection of IFN-–Producing Cells
The ELISPOT technique was used to determine the frequency of cells producing IFN- as described.18 29 30 Briefly, PBMCs from healthy donors were suspended in complete medium at a concentration of 2x105/mL. PAF, lyso-PAF, TT, WEB 2170, or oxLDL was added at the indicated concentrations, and cell suspensions were incubated at 37°C. Each measurement was performed in triplicate. After 72 hours, cells were washed three times in PBS, and 200 µL of the cell suspension was transferred to anti–IFN-–coated, 96-well nitrocellulose plates (Millititre HA; Millipore Corp). The frequency of cells producing IFN- was determined. Spots were counted under low magnification (x20) using an inverted microscope, each spot representing one IFN-–secreting cell.
Anti-MHC Class II Antibodies
MHC class II–dependent immune reactions were inhibited by a pool of three different mAbs reacting against human MHC class II, at a concentration of 1 µg/mL. This concentration has been shown to inhibit oxLDL and TT-induced IFN- production, as determined by ELISPOT to background levels (reviewed in Reference 1818 and also an unpublished observation). The pool consisted of equal amounts of 2.06 (mouse IgG1, anti-HLA DR), IVA 12 (IgG1, anti-HLA DR, DP, DQ), and 9,3F10 (IgG2a, anti-HLA DR, DQ), all from American Type Culture Collection.
Two mAbs directed against keyhole limpet hemocyanin were used as control antibodies for the MHC class II blocking experiments, clone H5 (IgG1) and clone 7-B4 (IgG2a; 31). Control antibodies were used in the same concentrations and ratios of IgG subclasses as for the blocking antibodies.
Determination of TNF- Production
For determination of TNF- with ELISA, whole blood from healthy volunteers was diluted 1:4 with serum-free RPMI-1640, while maintaining at 37°C, and then stimulated as indicated with PAF or oxLDL for 24 hours. We used an ELISA kit from Medgenix according to the manufacturer's instructions. Cell viability was determined by trypan blue exclusion and exceeded 95% in all experiments.
Statistics
Conventional methods were used for calculation of means and SDs. Comparisons between control samples and test samples were analyzed by Student's t test. Effects of PAF in the whole group tested was computed by use of Wilcoxon's signed rank test.
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Results |
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Effect of PAF and Lyso-PAF on IFN-
Secretion in PBMCsBy use of the ELISPOT assay, we found that PAF, in contrast to lyso-PAF, induced enhanced IFN-
secretion in 11 of 14 healthy blood donors tested. There was a considerable interindividual variation in IFN- secretion both at the basal level and with stimulation by PAF. At a concentration of 1 µg/mL, PAF was found to enhance the basal level of IFN- secretion by 197±111% (P<.05). An experiment demonstrating the effect of PAF and lyso-PAF on IFN- secretion of PBMCs in a high-responding individual is shown in Fig 1
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) or lyso-PAF (
). The frequency of IFN-
We tested the effect of mAbs to MHC class II on PAF-induced IFN- secretion to determine whether the effect of PAF depends on MHC class II. We found that 1 µg/mL of pooled anti-MHC class II antibodies added to the cell cultures completely abolished the PAF-induced IFN- secretion. The concentration of PAF needed to induce a maximal IFN- response varied between individuals, but in all cases the effect was inhibited by anti-MHC class II antibodies. Fig 2 shows a representative experiment in which MHC class II antibodies completely inhibited PAF-induced IFN- secretion. Control antibodies had no effect on either oxLDL- or PAF-induced IFN- secretion (data not shown).
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To determine whether PAF- and oxLDL-induced IFN- secretions were mediated by the PAF receptor, we tested whether a specific PAF-receptor antagonist, WEB 2170,31 inhibits PAF-induced effects demonstrated here. We found that WEB 2170 completely inhibited PAF-induced IFN- secretion in all individuals tested. Likewise, WEB 2170 inhibited oxLDL-induced IFN- secretion (Fig 3).
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), with addition of WEB 2170 at the indicated concentrations for 72 hours. Data are presented as increase in IFN-
TT is a strong antigen, and peptides thereof are recognized by T cells in the context of MHC class II. To determine the specificity of WEB 2170, the effect on TT-induced IFN- secretion was determined. Fig 4 shows that WEB 2170 had no effect on TT-induced IFN- secretion. Trace amounts of LPS are present in oxLDL, and to exclude the possibility that the effects described were caused by LPS, we tested the effects of LPS on IFN- secretion. No significant effects of LPS on IFN- secretion were noted even at concentrations more than 1000 times higher than those present in oxLDL (data not shown).
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Effect of PAF and OxLDL on TNF- Secretion
PAF induced enhanced TNF- production in diluted whole blood after 6 hours of culture, an effect abolished by WEB 2170 (Fig 5A). OxLDL also had the capacity to induce TNF- in this assay, an effect only partially inhibited by WEB 2170 (Fig 5B). LPS-induced TNF- secretion was not inhibited by WEB 2170 (data not shown).
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Discussion |
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In this study, we demonstrate that PAF has the capacity to induce enhanced IFN-
secretion in PBMCs, as determined by the highly sensitive ELISPOT technique. Antibodies to MHC class II inhibited PAF-induced IFN- secretion, which indicates that the stimulatory effect is mediated indirectly by accessory cells expressing MHC class II, in the context of which an antigen is presented. Both PAF- and oxLDL-induced IFN- secretion were inhibited by the specific PAF-receptor antagonist WEB 2170. This finding implies that these novel properties of PAF were mediated by the PAF receptor. Since PAF receptors are not present on lymphocytes in peripheral blood,21 the effects of PAF described are likely to be induced by the PAF receptor on monocytes. Recently, oxLDL has been shown to contain PAF-like lipids,23 and since the immune-stimulating properties of oxLDL were inhibited by WEB 2170, our findings imply that PAF-like lipids in oxLDL could be involved in activation of lymphocytes.
Lyso-PAF, which is generated by PAF acetylhydrolase, has none of the biological effects of PAF.19 In accordance with these observations, we also report that lyso-PAF did not share the IFN-–activating properties of PAF.
The IFN-–inducing effect of both PAF and oxLDL showed considerable variation between individuals, and it remains to be elucidated whether these effects differ between subjects with atherosclerosis and healthy persons.
The specificity of WEB 2170 for the PAF receptor was investigated by testing the effects on TT-induced IFN- secretion. TT is a conventional antigen not known to activate the PAF receptor. Therefore, the finding that WEB 2170 had no effect on TT-induced IFN- secretion shows that WEB 2170 is not an unspecific inhibitor of IFN- secretion. Trace amounts of endotoxin (LPS) are present in the lipoprotein preparations,18 and since LPS is a potent monocyte/macrophage activator, the possibility that LPS was involved in the reactions investigated here must be considered. However, LPS had no effect on IFN- secretion. Furthermore, WEB 2170 had no effect at all on LPS-induced TNF- secretion. It is therefore not likely that the effects described here are due to contamination by LPS.
We have demonstrated that oxLDL has the capacity to induce activation of monocytes, characterized by IL-1ß secretion, expression of macrophage differentiation markers, and enhanced adhesiveness.9 12 We report that both oxLDL and PAF induced TNF- secretion in peripheral blood, using an assay in which peripheral blood is diluted with medium, with no prior preparation of PBMCs with Ficoll-Paque. The main advantage of this assay is that stress during conventional preparation of monocytes, including multiple centrifugations, may influence the monocytes per se.34 TNF- is a potent monokine, with multiple effects on several biological functions, including enhancing the adhesiveness of endothelial cells, potentiation of immune reactions, and increasing insulin resistance, which is present in the metabolic syndrome associated with atherosclerosis.35 OxLDL-stimulated PBMCs enhance the expression of adhesion molecules in endothelial cells,36 and both IL-1 and TNF- have this capacity, making these cytokines likely candidates to explain these oxLDL-mediated effects. Our finding that WEB 2170 completely inhibited PAF-induced but only partially inhibited oxLDL-induced TNF- indicates that other components of oxLDL than PAF-like lipids also may participate in monocyte activation.
The mechanisms by which PAF and PAF-like lipids activate immune-competent cells remain to be elucidated. The lymphocyte activation demonstrated here is likely to be mediated by monocytes and to depend on an antigen, since it is MHC class II dependent.
During oxidation of LDL, apoB100 in LDL undergoes profound changes, and novel epitopes of this protein may be exposed.37 38 39 In principle, fragments of apoB100 may therefore be immunogenic. However, since oxLDL-induced IFN- secretion was inhibited by WEB 2170, factors in the lipid component of oxLDL may in itself explain the IFN-–stimulatory capacity of oxLDL.
In general, lipids have not been regarded as antigens, but recently it has been demonstrated that mycolic acid, a free fatty acid present in mycobacterial tuberculosis, can in itself be presented on macrophages and recognized by T cells.40 The possibility that lipid components in PAF or PAF-like lipids present in oxLDL could be T-lymphocyte antigens presented in the context of MHC class II can therefore not be excluded. Against this stands the finding that mycolic acid–induced T-lymphocyte activation is not mediated by MHC class II but instead by CD1, and hitherto, lipids have not been shown to activate T cells by MHC class II.
The effects described here may in principle be due to a cytokine-like, unspecific effect of PAF and PAF-like lipids in oxLDL, although the MHC class II dependency argues against this. It is also possible that PAF and PAF-like lipids in oxLDL further activate T cells already stimulated by other antigens.
Another possibility is that epitopes induced on monocytes are immunogenic, the most likely candidate being one or several hsp's.41 We have recently found that oxLDL induces hsp60 in monocytic cells.42 In addition, hsp60-reactive T cells are present in normal control individuals,43 and stressed macrophages are recognized by T cells specific for hsp.44 We have recently demonstrated that hyperthermia may induce signs of immune activation in vitro, an effect most likely dependent on hsp's.45 It is therefore possible that oxLDL induces hsp60, which is recognized by specific T cells. This hypothesis is compatible with recent findings implying that immunization with hsp60 induces enhanced atherosclerosis in experimental animals.46
Recently, oxLDL has been shown to activate T-cell clones from atherosclerotic plaques.17 It remains to be elucidated whether this activation depends on PAF-like lipids or modified forms of apoB100.
The finding that PAF activates lymphocytes, leading to IFN- secretion, may be of importance in several inflammatory conditions, including asthma and vasculitis.
IFN- has several properties fundamental in inflammatory and immune reactions, including macrophage activation and induction of MHC class II on accessory cells. In atherogenesis, therefore, PAF- or oxLDL-induced IFN- may play an important role by potentiating an immune response in the artery wall. On the other hand, IFN- inhibits smooth muscle cell growth and suppresses foam cell formation.47 Furthermore, IFN- inhibits the expression of 15-lipoxygenase, which oxidizes LDL.48 In experimental animals, immunization with hsp60 aggravates atherosclerosis,46 but oxLDL reduces atherosclerosis.49 These findings indicate that the immune system modulates the development of atherosclerosis. The role of IFN- and activated T cells may therefore be complex in atherosclerosis, and it is possible that the final outcome of an immune reaction in the artery wall depends on the balance between the various reactions and cytokines induced in the early inflammatory atherosclerotic lesion.
Our findings demonstrate striking similarities in the proinflammatory properties of oxLDL and PAF and point to an important role of the PAF receptor in mediating the effects of oxLDL.
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Acknowledgments |
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This work was supported by King Gustaf V 80th Birthday Fund, the Swedish Society of Medicine, Osterman's Fund, The Swedish Rheumatism Association, Wiberg's Fund, Dahlén's Fund, Salén's Fund, and the Nanna Svartz Fund. The PAF-receptor antagonist WEB 2170 was a kind gift from Boehringer-Ingelheim, Ingelheim-am-Rhein, Germany.
Received November 29, 1995; accepted August 8, 1996.
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References |
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|---|
1. Morley J, Sanjar S, Page CP, Bretz U. The role of circulating cells in skin reactions. Br J Dermatol. 1985;113:86-90.
2. Warren JS, Mandel DM, Johnson KJ, Ward PA. Evidence for the role of platelet-activating factor in immune complex vasculitis in the rat. J Clin Invest. 1989;83:669-678.
3. Evangelou AM. Platelet-activating factor (PAF): Implications for coronary heart and vascular diseases. Prostaglandins Leukot Essent Fatty Acids. 1994;50:1-28.[Medline] [Order article via Infotrieve]
4.
Vivier E, Deryckx S, Wang JL, Valentin H, Peronne C, de Vries JE, Bernard A, Benveniste J, Thomas Y. Immunoregulatory functions of paf-acether, VI: Inhibition of T cell activation via CD3 and potentiation of T cell activation via CD2. Int Immunol. 1990;2:545-553.
5. Behrens TW, Goodwin JS. Control of human T cell proliferation by platelet-activating factor. Int J Immunopharmacol. 1990;12:175-184.[Medline] [Order article via Infotrieve]
6. Bourgain RH, Maes C, Braquet P, Andries R, Torqui L, Braquet M. The effect of 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF-acether) on the arterial wall. Prostaglandins. 1985;30:185-197.[Medline] [Order article via Infotrieve]
7. Feliste R, Perret B, Braquet P, Chap H. Protective effect of BN 52021, a specific antagonist of platelet-activating factor (PAF-acether), against diet-induced cholesteryl ester deposition in rabbit aorta. Atherosclerosis. 1989;78:151-158.[Medline] [Order article via Infotrieve]
8.
Stafforini DM, McIntyre TM, Carter ME, Prescott SM. Human plasma platelet-activating factor acetylhydrolase: association with lipoprotein particles and role in the degradation of platelet-activating factor. J Biol Chem. 1987;262:4215-4222.
9. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801-809.[Medline] [Order article via Infotrieve]
10. Libby P, Hansson GK. Biology of disease: involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Invest. 1991;64:5-15.[Medline] [Order article via Infotrieve]
11. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915-924.[Medline] [Order article via Infotrieve]
12.
Hessler JR, Morel DW, Lewis J, Chisholm GM. Lipoprotein oxidation and lipoprotein-induced cytotoxicity. Arteriosclerosis. 1983;3:215-222.
13. Berliner JA, Territo MC, Sevanian A, Ramin S, Kim JA, Bamshad B, Esterson M, Fogelman AM. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest. 1990;85:1260-1266.
14. Frostegård J, Haegerstrand A, Gidlund M, Nilsson J. Biologically modified low density lipoprotein increases the adhesive properties of vascular endothelial cells. Atherosclerosis. 1991;90:119-126.[Medline] [Order article via Infotrieve]
15.
Frostegård J, Nilsson J, Haegerstrand A, Hamsten A, Wigzell H, Gidlund M. Oxidized low-density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937. Proc Natl Acad Sci U S A. 1990;87:904-908.
16.
Frostegård J, Wu R, Giscombe R, Holm G, Lefvert AK, Nilsson J. Induction of T cell activation by oxidized low density lipoprotein. Arterioscler Thromb. 1992;12:461-467.
17. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1995;92: 3893-3897.
18.
Huang YH, Rönnelid J, Frostegård J. Oxidized LDL induces enhanced antibody formation and MHC class II–dependent IFN- production in lymphocytes from healthy individuals. Arterioscler Thromb Vasc Biol. 1995;15:1577-1583.
19. Bonavida B, Mencia-Huerta JM, Braquet P. Effect of platelet-activating factor (PAF) on monocyte activation and production of tumor necrosis factor. Int Arch Allergy Applied Immunol. 1989;88:157-160.[Medline] [Order article via Infotrieve]
20.
Kunz D, Gerard NP, Gerard CJ. The human leukocyte platelet-activating factor receptor: cDNA cloning, surface expression, and construction of a novel epitope-bearing analog. J Biol Chem. 1992;267:9101-9106.
21. Simon HU, Tsao PW, Siminovitch KA, Mills GB, Blaser K. Functional platelet-activating factor receptors are expressed by monocytes and granulocytes but not by resting or activated T and B lymphocytes from normal individuals or patients with asthma. J Immunol. 1994;153:364-377.[Abstract]
22. Calabresse C, Njuer MC, Pellegrini O, Benveniste J, Richiard Y, Thomas Y. Induction of high-affinity paf receptor expression during T cell activation. Eur J Immunol. 1992;22:1349-1355.[Medline] [Order article via Infotrieve]
23. Korth R, Zimmermann K, Richter WO. Lipoprotein-associated paf (LA-paf) was found in washed human platelets and monocyte/ macrophage-like U937 cells. Chem Phys Lipids. 1994;70:109-119.[Medline] [Order article via Infotrieve]
24. Tokumura A. A family of phospholipid autacoids: occurrence, metabolism and bioactions. Prog Lipid Res. 1995;34:151-184.[Medline] [Order article via Infotrieve]
25.
Lehr HA, Seemuller J, Hubner C, Menger MD, Messmer K. Oxidized LDL-induced leukocyte/endothelium interaction in vivo involves the receptor for platelet activating factor. Arterioscler Thromb. 1993;13:1013-1018.
26. Watson AD, Navab M, Hama SY, Sevanian A, Prescott AM, Stafforini DM, McIntyre TM, La Du BN, Fogelman A, Berliner JA. Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized low density lipoprotein. J Clin Invest. 1995;95:774-782.
27. Havel RJ, Eder HA, Bragdon JH. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955;34:1345-1353.
28.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:265-275.
29. Kabilan L, Andersson G, Lolli F, Ekre HP, Olsson T, Troye-Blomberg M. Detection of intracellular expression and secretion of interferon-gamma at the single cell level after activation of human T cells with tetanus toxoid in vitro. Eur J Immunol. 1990; 20:1085-1089.
30.
Czerkinsky C, Andersson G, Ekre HP, Nilsson LA, Klareskog L, Ouchterlony Ö. Reverse ELISPOT assay for clonal analysis of cytokine production, I: enumeration of -interferon–secreting cells. J Immunol Methods. 1988;110:29-36.[Medline]
[Order article via Infotrieve]
31. Coulie PG, Van Snick J. Enhancement of IgG anti-carrier responses by IgG2 anti-hapten antibodies in mice. Eur J Immunol. 1985;15:793-798.[Medline] [Order article via Infotrieve]
32. Heuer H, Birke F, Brandt K, Muacevic G, Weber KH. Biological characterization of the enantiomeric hetrazepines of the paf-antagonist WEB 2170. Prostaglandins. 1988;35:847. Abstract.
33. Rola-Pleszczynski M, Pignol B, Pouliot C, Braquet P. Inhibition of human lymphocyte proliferation and interleukin 2 production by platelet activating factor (PAF-acether): reversal by a specific antagonist, BN 52021. Biochem Biophys Res Commun. 1987;142: 754-760.
34. Lundahl J, Hallden G, Hallgren M, Skold CM, Hed J. Altered expression of CD11b/CD18 and CD62 L on human monocytes after cell preparation procedures. J Immunol Methods. 1995;180:93-100.[Medline] [Order article via Infotrieve]
35.
Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A. 1994;91:4854-4858.
36. Frostegård J, Wu R, Haegerstrand A, Patarroyo M, Lefvert AK, Nilsson J. Mononuclear leukocytes exposed to oxidized low density lipoprotein secrete a factor that stimulates endothelial expression of adhesion molecules. Atherosclerosis. 1993;103:213-219.[Medline] [Order article via Infotrieve]
37. Jürgens G, Hoff HF, Chisolm GM, Esterbauer H. Modification of human serum low density lipoprotein by oxidation: characterization and pathophysiological implications. Chem Phys Lipids. 1987;45: 315-336.
38. Esterbauer H, Jürgens G, Quehenberger O, Koller E. Autooxidation of human low density lipoprotein: loss of polyunsaturated fatty acids and vitamin E and generation of aldehydes. J Lipid Res. 1987;28:495-509.[Abstract]
39. Halliwell B. How to characterize a biological antioxidant. Free Radic Res Commun. 1990;9:1-32.[Medline] [Order article via Infotrieve]
40. Beckman EM, Porcelli SA, Morita CT, Behar SM, Furlong ST, Brenner MB. Recognition of a lipid antigen by CD1 restricted AB+ T cells. Nature. 1995;372:691-694.
41. Kiessling R, Grönberg A, Ivanyi J, Söderström K, Ferm M, Kleinau S, Nilsson E, Klareskog L. Role of hsp60 during autoimmune and bacterial inflammation. Immunol Rev. 1991;12:91. Abstract.
42. Frostegård J, Kjellman B, Gidlund M, Andersson B, Jindal S, Kiessling R. Induction of heat shock protein in monocytic cells by oxidized low density lipoprotein. Atherosclerosis. 1996;121: 93-103.
43.
Lamb JR, Bal V, Mendez-Sampeiro P, Mehlert A, So A, Rothbard J, Jindal S, Young RA, Young DB. Stress proteins may provide a link between the immune response to infection and autoimmunity. Int Immunol. 1989;1:1. Abstract.
44.
Koga T, Wand-Wurttenberger A, De Bruyn J, Munk ME, Schoel B, Kaufmann SH. T cells against a bacterial heat shock protein recognize stressed macrophages. Science. 1989;245:1112-1115.
45. Huang YH, Haegerstrand A, Frostegård J. Effects of in vitro hyperthermia on proliferative responses and lymphocyte activity. Clin Exp Immunol. 1996;103:61-67.[Medline] [Order article via Infotrieve]
46.
Xu Q, Oberhuber G, Gruschwitz M, Wick G. Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. Arterioscler Thromb. 1992;12:789-799.
47.
Wilson AC, Schaub RG, Goldstein RC, Kuo PT. Suppression of aortic atherosclerosis in cholesterol-fed rabbits by purified rabbit interferon. Arteriosclerosis. 1989;10:208-214.
48.
Conrad DJ, Kühn H, Mulkins M, Highland E, Sigal E. Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase. Proc Natl Acad Sci U S A. 1995;89:217-221.
49.
Palinski W, Miller E, Witztum J. Immunization of low density lipoprotein (LDL) receptor deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci U S A. 1995;92:821-825.
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 P. Turunen, J. Jalkanen, T. Heikura, H. Puhakka, J. Karppi, K. Nyyssonen, and S. Yla-Herttuala Adenovirus-mediated gene transfer of Lp-PLA2 reduces LDL degradation and foam cell formation in vitro J. Lipid Res., September 1, 2004; 45(9): 1633 - 1639. [Abstract] [Full Text] [PDF]
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 J. B. Sedgwick, Y. S. Hwang, H. A. Gerbyshak, H. Kita, and W. W. Busse Oxidized Low-Density Lipoprotein Activates Migration and Degranulation of Human Granulocytes Am. J. Respir. Cell Mol. Biol., December 1, 2003; 29(6): 702 - 709. [Abstract] [Full Text] [PDF]
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B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF]
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 E Svenungsson, G-Z Fei, K Jensen-Urstad, U de Faire, A Hamsten, and J Frostegard TNF-{alpha}: a link between hypertriglyceridaemia and inflammation in SLE patients with cardiovascular disease Lupus, June 1, 2003; 12(6): 454 - 461. [Abstract] [PDF]
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 K. Y. Stokes, E. C. Clanton, K. P. Clements, and D. N. Granger Role of Interferon-{gamma} in Hypercholesterolemia-Induced Leukocyte-Endothelial Cell Adhesion Circulation, April 29, 2003; 107(16): 2140 - 2145. [Abstract] [Full Text] [PDF]
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S. M. Prescott, T. M. McIntyre, G. A. Zimmerman, and D. M. Stafforini Sol Sherry Lecture in Thrombosis: Molecular Events in Acute Inflammation Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 727 - 733. [Abstract] [Full Text] [PDF]
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G. K. Hansson Immune Mechanisms in Atherosclerosis Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1876 - 1890. [Abstract] [Full Text] [PDF]
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 R. Wu, C. Lemne, U. de Faire, and J. Frostegard Antibodies to Lysophosphatidylcholine Are Decreased in Borderline Hypertension Hypertension, January 1, 2001; 37(1): 154 - 159. [Abstract] [Full Text] [PDF]
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P. M. Morganelli, S. M. Kennedy, and T. I. Mitchell Differential effects of interferon-{gamma} on metabolism of lipoprotein immune complexes mediated by specific human macrophage Fc{gamma} receptors J. Lipid Res., March 1, 2000; 41(3): 405 - 415. [Abstract] [Full Text]
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 M. Y. Chang, S. Potter-Perigo, C. Tsoi, A. Chait, and T. N. Wight Oxidized Low Density Lipoproteins Regulate Synthesis of Monkey Aortic Smooth Muscle Cell Proteoglycans That Have Enhanced Native Low Density Lipoprotein Binding Properties J. Biol. Chem., February 18, 2000; 275(7): 4766 - 4773. [Abstract] [Full Text] [PDF]
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T. M. McIntyre, G. A. Zimmerman, and S. M. Prescott Biologically Active Oxidized Phospholipids J. Biol. Chem., September 3, 1999; 274(36): 25189 - 25192. [Full Text] [PDF]
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R. Wu, U. de Faire, C. Lemne, J. L. Witztum, and J. Frostegard Autoantibodies to OxLDL Are Decreased in Individuals With Borderline Hypertension Hypertension, January 1, 1999; 33(1): 53 - 59. [Abstract] [Full Text] [PDF]
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J. Frostegard, R. Wu, C. Gillis-Haegerstrand, C. Lemne, and U. de Faire Antibodies to Endothelial Cells in Borderline Hypertension Circulation, September 15, 1998; 98(11): 1092 - 1098. [Abstract] [Full Text] [PDF]
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