Published online before print December 22, 2005, doi: 10.1161/01.ATV.0000201041.14438.8d
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© 2006 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
OxLDL–IgG Immune Complexes Induce Survival of Human Monocytes
From Wihuri Research Institute (R.O., P.T.K., K.A.L., M.O.P.), Helsinki, Finland, and BioInvent International AB (B.J.), Lund, Sweden.
Correspondence to Petri T. Kovanen, Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland. E-mail petri.kovanen{at}wri.fi
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Abstract |
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Objective— Immune complexes containing oxidatively modified low-density lipoprotein (oxLDL) particles are deposited in human atherosclerotic lesions during atherogenesis. Here we studied whether OxLDL–IgG immune complexes (OxLDL–IgG ICs) affect survival of human monocytes.
Methods and Results— As demonstrated by light microscopy, and analysis of cell proliferation, caspase-3 activity, and DNA fragmentation, OxLDL–IgG ICs promoted survival of cultured human monocytes by decreasing their spontaneous apoptosis. OxLDL–IgG ICs induced a concentration-dependent production of the major monocyte growth factor, monocyte colony-stimulating factor (M-CSF), by the monocytes, but its inhibition was without effect on OxLDL–IgG IC–induced monocyte survival. Rather, OxLDL–IgG ICs induced rapid phosphorylation of Akt, suggesting a direct anti-apoptotic effect mediated by cross-linking of Fc
receptors. Experiments with receptor blocking antibodies revealed that the OxLDL–IgG IC–induced monocyte survival was mediated by Fc receptor I.
Conclusions— The results show that OxLDL–IgG ICs promote survival of monocytes by cross-linking Fc receptor I and activating Akt-dependent survival signaling. The results reveal a novel mechanism by which an immune reaction toward oxLDL can play a role in the accumulation of macrophages in human atherosclerotic lesions.
Immune complexes containing oxidatively modified low-density lipoprotein (oxLDL) particles are deposited in human atherosclerotic lesions during atherogenesis. Here we show that OxLDL–IgG immune complexes (OxLDL–IgG ICs) promote the survival of monocytes, independently of produced M-CSF, by cross-linking Fc receptor I and activating Akt-dependent survival signaling.
Key Words: atherosclerosis • monocytes • oxLDL
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Introduction |
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Atherosclerosis is characterized by early accumulation of lipids and macrophages in the intimal layer of the arterial wall. Lipids, mainly derived from serum low-density lipoprotein (LDL) particles, accumulate in the extracellular matrix of the intima, were they are exposed to various modifications, such as oxidation.1 The process may begin early in life as epitopes of oxLDL are found the aortic intima of human fetuses of hypercholesterolemic women, and this is followed by infiltration of monocytes in the intima.2 OxLDL is recognized and taken up by macrophages via scavenger receptors, which are then transformed into lipid-filled foam cells. Modified lipids on the surface of oxLDL are biologically active and are recognized by various pattern recognition receptors of the innate immune system, notably by the Toll-like receptor 4 (TLR4).3,4 OxLDL is also able to activate the adaptive immune system when antigen-presenting cells present peptides derived from oxLDL particle on MHC class II molecules for recognition by CD4+ T cells,5 which then leads to the production of antibodies specific for oxLDL. Consistently, human atherosclerotic lesions contain clones of CD4+ T cells that recognize epitopes of oxLDL and respond to oxLDL stimulation by proliferation and cytokine production.6 Moreover, antibodies against oxLDL are present in the circulation, and their levels have been shown to correlate positively with cardiovascular disease and its complications.7–9 Human atherosclerotic lesions also contain IgG that recognizes oxLDL and OxLDL–IgG immune complexes (OxLDL–IgG IC).10 When added to cultured macrophages, OxLDL–IgG ICs promote foam cell formation and induce the production of proinflammatory cytokines, oxygen radicals, and matrix metalloproteinases by the macrophages.11–13
Infiltration of monocytes into the arterial intima involves their attachment to activated endothelium via vascular cell adhesion molecule (VCAM)-1, and transmigration into the intima, where the monocytes differentiate into tissue macrophages.14,15 This process requires both chemotactic and growth-promoting factors. Monocyte chemotactic protein-1 (MCP-1) is the best-characterized chemokine for monocytes, and its expression in the arterial intima has been shown to be critical for the development of atherosclerotic lesions in mice.16 Monocyte colony-stimulating factor (M-CSF), again, appears to be the critical growth factor for macrophage survival and differentiation.17 Thus, M-CSF has been detected in human atherosclerotic lesions both at mRNA and protein level,18,19 and M-CSF deficiency has been shown to result in significantly reduced atherosclerosis in different mouse models of atherosclerosis.20–23
The initial observation that immobilized nonspecific IgG can trigger the production of M-CSF by monocytes24 suggested to us that also OxLDL–IgG ICs, in which the IgG-molecules are immobilized, could promote monocyte survival. We have now studied the effect of OxLDL–IgG ICs on the monocyte survival, and also attempted to identify the receptors and downstream signaling events involved in this process.
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Materials and Methods |
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Please see http://atvb.ahajournals.org for full Materials and Methods section.
Human LDL was isolated from plasma of healthy volunteers by sequential ultracentrifugation.25 LDL was oxidized with copper by incubation LDL (1 mg/mL) with 10 µmol/L CuSO4 at 37°C for 18 hours. Insoluble ICs were prepared by incubating rabbit anti-LDL antibody (affinity-purified IgG; 200 µg/mL) with oxLDL (125 µg/mL) in sterile phosphate-buffered saline overnight at 4°C. After incubation, the precipitate was centrifuged at 10 000 rpm and resuspended in sterile phosphate-buffered saline. To prepare native LDL-IgG ICs and keyhole limpet hemocyanin (KLH)-IgG ICs, oxLDL was replaced with native LDL (nLDL), and rabbit anti-KLH antibody (affinity-purified IgG; 250 µg/mL; Sigma) was incubated together with KLH (125 µg/mL; Sigma), respectively. In some studies, human recombinant monoclonal IgG1 antibodies against MDA-modified apoB-100–derived peptides (a kind gift from Dr B. Jansson, BioInvent International AB, Lund, Sweden) or anti-oxLDL antibodies isolated from human serum were added to cells either alone (25 µg/mL), or together with oxLDL (15 µg/mL), either in the absence or presence of F(ab)2 fragment of goat anti-human IgG (25 µg/mL; Sigma).
Human mononuclear leukocytes from healthy subjects were isolated from buffy coats (obtained from the Finnish Red Cross, Helsinki, Finland) by Ficoll-Paque gradient centrifugation. No added serum or added growth factors were present at any stage of culture. The monocytes were stimulated by insoluble OxLDL–IgG ICs at concentrations ranging from 5 to 50 µg/mL. Control stimuli included oxLDL or rabbit anti-LDL alone, lipopolysaccharide (LPS) 100 pg/mL, and 10 ng/mL granulocyte macrophage colony-stimulating factor (GM-CSF) (Gibco) or 10 ng/mL M-CSF (R&D Systems, Minneapolis, Minn). After 48-hour incubation, the morphology of cells was analyzed by phase-contrast microscopy, and the samples were collected according to the requirements of further analysis, which included quantifying the viability of the monocytes, production of M-CSF by monocytes, and proliferation and apoptosis of monocytes. Akt phosphorylation was studied in cell lysates by Western blot analysis.
To study which receptors were involved in the OxLDL–IgG IC-mediated effects on monocytes, the monocytes were pre-incubated with F(ab)2 fragments of 20 µg/mL mouse anti-human CD64 (Ancell, Bayport, Minn), and 20 µg/mL mouse anti-human CD32 (Ancell) before addition of OxLDL–IgG ICs. To verify that Akt-dependent pathway was involved in OxLDL–IgG IC-induced monocyte survival, the activation of this pathway was blocked by the inhibitor of PI3-kinase LY294002 (Calbiochem, Darmstadt, Germany) 1 hour before addition of OxLDL–IgG ICs (25 µg/mL).
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Results |
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OxLDL–IgG ICs Induce Monocyte Survival
In the absence of growth factors in the culture medium, isolated monocytes rapidly undergo apoptotic cell death. To study the effect of OxLDL–IgG ICs on monocyte survival, monocytes isolated from human buffy coats were plated and incubated in serum-free medium devoid of growth factors for 18 hours. Thereafter, the monocytes were incubated for 48 hours in serum-free medium in the absence or presence of OxLDL–IgG ICs (50 µg/mL). In the absence of OxLDL–IgG ICs, a fraction of the attached monocytes were detached. The morphology of the remaining attached monocytes was heterogenous in that most of them showed shrunken morphology (Figure 1A, left panel). In contrast, the monocytes stimulated by the OxLDL–IgG ICs remained attached to the bottom of the well, were large, and spread along the surface of the well (Figure 1A, right panel). To quantify the effect of OxLDL–IgG ICs on monocyte survival, the number of viable monocytes was analyzed by measuring their metabolic activity (WST assay). As shown in Figure 1B, stimulation by OxLDL–IgG ICs (50 µg/mL) significantly (P<0.05) increased the number of viable cells when compared with unstimulated cells (negative control), or stimulation by oxLDL (10 µg/mL), rabbit anti-LDL antibody (40 µg/mL), or LPS (100 pg/mL). The effect on monocyte survival is not specific for oxLDL, because immune complexes containing nLDL or KLH were also able to induce similar increases in the number of viable monocytes (Figure 1C). Importantly, addition of 5% interstitial fluid did not affect the results (Figure I, available online at http://atvb.ahajournals.org), suggesting that OxLDL–IgG ICs can affect monocyte survival also under conditions closely mimicking those prevailing in the human arterial intima. Similarly, addition of 1% albumin had no effect on the results (not shown). Oil Red O-staining (not shown) revealed that addition of OxLDL–IgG ICs to monocytes lead to the accumulation of lipid droplets inside the cells, which partly explained their foam cell-like morphology (see Figure 1A). HPTLC analysis (Figure II, available online at http://atvb.ahajournals.org) showed that OxLDL–IgG ICs led to &2-fold increase (P<0.05) in the content of free and &9-fold increase (P<0.05) in the content of esterified cholesterol in the cells when compared with untreated cells. In contrast, oxLDL, AcLDL or nLDL did not increase the cholesterol-content of the monocytes.
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OxLDL–IgG ICs Protect Monocytes From Apoptosis
We next studied whether the increased number of viable monocytes resulted from increased cellular proliferation or decreased level of cellular apoptosis. First, we quantified the degree of proliferation by (methyl-3H)-thymidine incorporation assay. We were not able to detect any proliferation in monocytes cultured in the absence or presence of OxLDL–IgG ICs (15 µg/mL) or GM-CSF (10 ng/mL) (not shown). To analyze apoptotic DNA fragmentation, monocytes were cultured in the presence or absence of OxLDL–IgG ICs (25 µg/mL) for 48 hours, after which the DNA fragmentation was analyzed by commercial quantitative sandwich-enzyme-linked immunoassay. As shown in Figure 2A, addition of OxLDL–IgG ICs to the monocytes strongly reduced their DNA fragmentation (by 43%; P<0.05) to the level observed in the presence of GM-CSF (10 ng/mL). Similarly, as shown in Figure 2B, the levels of active caspase-3 in OxLDL–IgG IC-treated cells were also strongly reduced (by 55%; P<0.05). Finally, we performed annexin V staining to visually analyze the apoptotic changes in monocytes (Figure 2C). By microscopic analysis, IC-treated cells showed less nuclear fragmentation and less annexin V-positive staining than the control cells cultured in the absence of OxLDL–IgG ICs.
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OxLDL–IgG ICs Induce M-CSF Production by Monocytes
Because OxLDL–IgG ICs induced survival of monocytes in culture, we studied whether this effect was mediated by the production of the major monocyte growth factor, monocyte colony-stimulating factor (M-CSF). As shown in Figure 3A, OxLDL–IgG ICs induced a concentration-dependent increase in the production of M-CSF by monocytes when compared with the untreated cells or cells stimulated by oxLDL (10 µg/mL) or rabbit anti-LDL antibody (40 µg/mL) alone. In this experiment, the concentrations of oxLDL and anti-LDL antibody were chosen to match to their concentrations in OxLDL–IgG ICs, when the ICs were added at the concentration of 50 µg/mL. Furthermore, to determine whether M-CSF was the mediator of OxLDL–IgG IC-induced survival of monocytes, the effect of this growth factor was blocked by a neutralizing antibody, and cell survival was analyzed by quantifying the number of viable cells. As shown in Figure 3B, addition of 10 µg/mL of the anti–M-CSF antibody (labeled as ab) efficiently blocked the M-CSF–induced (10 ng/mL) monocyte survival (b versus c; P<0.05) but had no effect on IC-induced survival (e versus f). Isotype-matched control antibodies (labeled ctrl ab) had no effect on M-CSF–induced or IC-induced monocyte viability (b versus d and e versus g).
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Akt Phosphorylation Is Essential for OxLDL–IgG IC-Induced Monocyte Survival
As demonstrated by the use of blocking antibody, the production of M-CSF was not involved in OxLDL–IgG IC-induced monocyte survival. Therefore, we studied the effect of OxLDL–IgG ICs on the activation of the central survival factor Akt in monocytes. The monocytes were cultured in the presence or absence of OxLDL–IgG ICs (50 µg/mL) or M-CSF (10 ng/mL) for 10 to 30 minutes, and the phosphorylation of Akt was analyzed by Western blotting. As shown in Figure 4A, the addition of OxLDL–IgG ICs to monocytes lead to a 2.7-fold increase in the phosphorylation of Akt (P<0.05) when compared with control cells cultured in the absence of ICs. This effect of was not dependent on the oxLDL component in the ICs as similar results were also obtained with KLH-IgG ICs (not shown). As controls, oxLDL and rabbit IgG alone did not induce phosphorylation of Akt. The level of Akt phosphorylation in IC-treated monocytes was comparable to the level in cells cultured in the presence of M-CSF, whereas it was independent of the total level of Akt. At this stage, ie, after 30 minutes of incubation, no M-CSF was detectable in the culture media of OxLDL–IgG IC-treated monocytes by commercial enzyme-linked immunosorbent assay (ELISA) method. To further exclude the possibility that very low amounts of M-CSF could have affected the phosphorylation result, we added to monocytes 9 pg/mL of M-CSF, which was the detection level in the used ELISA method. This amount of M-CSF, which might have been present in IC-stimulated cells, had no effect in Akt phosphorylation (not shown). To verify the role of Akt-pathway on OxLDL–IgG IC-induced monocyte survival, Akt-dependent pathway was blocked by PI3K-inhibitor LY294002 before addition of ICs. LY294002 caused a concentration-dependent inhibition on OxLDL–IgG IC-induced monocyte survival, and as shown in Figure 4B, 40 µg/mL of LY294002 totally abolished the effect of oxLDL ICs (25 µg/mL; P<0.05) and M-CSF (10 ng/mL; P<0.05) on monocyte survival.
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The Effect of OxLDL–IgG ICs on Monocyte Survival Is Mediated by Fc Receptor I
To elucidate the receptors potentially recognizing OxLDL–IgG ICs and mediating their effect on monocyte survival, the monocytes were pre-incubated with F(ab)2 fragments of blocking antibodies against Fc receptors I and II (FcR I and II) before incubating the cells with 25 µg/mL of OxLDL–IgG ICs. The results (Figure 5) show that blocking of FcRI (anti-CD64) resulted in strong decrease in the number of viable cells (by 68%; P<0.05), whereas blocking of FcRII (anti-CD32) decreased the viability of the cells to a lesser degree (by 23%), with this inhibition being statistically nonsignificant. Irrelevant isotype control (labeled as ctrl ab) had no effect on IC-induced monocyte survival.
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Immune Complexes Containing Human Recombinant Antibodies Against oxLDL Also Induce Monocyte Survival
Because these results on IC-induced monocyte survival were generated by using ICs containing rabbit IgGs, we found it necessary to verify the results by using human OxLDL–IgG ICs. For this purpose, we used human IgG1 recombinant antibodies, which had been generated against MDA-modified apoB-100–derived peptides (anti-MDA–apoB; clones LDO 107 Z3 IEI-E3 or CT-17)26 or human anti-oxLDL antibodies isolated from human serum. We incubated monocytes with human anti-oxLDL antibodies (25 µg/mL) either alone or together with oxLDL (15 µg/mL) either in the absence or presence of F(ab)2 fragment of goat anti-human IgG (Fab). As shown in Figure 6, neither one of the human recombinant antibodies alone (IEI-E3 or CT-17) was able to increase the monocyte survival (a versus d; a versus g). Similarly, the addition of either antibody together with oxLDL to the monocytes failed to increase the monocyte survival (a versus e; a versus h). This failure was probably caused by the small size of the formed immune complexes, because when immune complexes were rendered large and insoluble by addition of F(ab)2 fragments of goat anti-human IgG, monocyte survival was increased. This result was highly significant, with a 4.5-fold increase with the ICs containing the clone LDO 107 Z3 IEI-E3 (a versus f; P<0.01) and with a 2.2-fold increase with ICs containing the clone CT-17 (a versus i; P<0.01). Similar significant results were obtained by using anti-oxLDL antibodies isolated from the serum (not shown).
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Discussion |
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Atherosclerotic lesions contain immune complexes composed of oxLDL and IgG.10 We found that addition OxLDL–IgG ICs to freshly isolated human monocytes increased their survival, as detected by microscopic analysis and by measuring cell viability. This effect was found to be caused by decreased level of apoptosis of the OxLDL–IgG IC-treated cells. Moreover, OxLDL–IgG ICs induced a significant concentration-dependent increase in the production of M-CSF by the treated monocytes, but to our surprise, this was not essential for the OxLDL–IgG IC-mediated monocyte survival. Rather, direct cross-linking of monocyte Fc
RI was the likely mechanism behind the anti-apoptotic effect of OxLDL–IgG ICs. This notion is strongly supported by the following findings: (1) blocking of FcRI blocked the anti-apoptotic effect; (2) formation of large immune complexes capable of cross-linking FcRs was necessary for the anti-apoptotic effect; and (3) activation of the survival signaling (phosphorylation of Akt) occurred rapidly after addition of OxLDL–IgG ICs. The anti-apoptotic effect of OxLDL–IgG ICs was not dependent on the presence of oxLDL in the complexes; however, in the presence of oxLDL the cells effectively transformed into foam cells, a hallmark of early atherosclerosis.
In the absence of growth factors, either M-CSF or GM-CSF, monocytes undergo spontaneous apoptosis via the mitochondrial (intrinsic) pathway, leading to activation of caspases 9 and 3, and subsequent DNA fragmentation.27,28 Although previous studies have shown that oxLDL alone at low concentrations can promote cell survival, by both inhibiting acid sphingomyelinase and increasing BclXL,29 and at higher concentrations promote apoptosis,30–33 in our experiments oxLDL alone did not affect macrophage survival. However, we found that when oxLDL had been complexed with IgGs, the amount of active caspase-3 and DNA fragmentation were reduced to levels comparable to cells cultured merely in the presence of growth factors, either M-CSF or GM-CSF. Interestingly, OxLDL–IgG ICs also induced a concentration-dependent increase in the production of M-CSF by monocytes. M-CSF exerts its anti-apoptotic effect by activating the PI 3-kinase–dependent pathway resulting in the phosphorylation of Akt, a central survival factor in monocytes.34 Phosphorylated Akt, in turn, inhibits the mitochondrial apoptotic pathway by phosphorylating (and thereby inactivating) the proapoptotic factor BAD35 and procaspase-9.36 Of great interest, cross-linking of mouse FcRs with monoclonal antibodies has been shown to lead to PI 3-kinase activation and Akt phosphorylation.37 Accordingly, we hypothesized that the anti-apoptotic effect of the OxLDL–IgG ICs was mediated either via secretion of M-CSF or via a direct effect of the ICs on Akt phosphorylation. Our finding of a rapid phosphorylation of Akt after addition of OxLDL–IgG ICs and of inhibition of monocyte survival by blocking of the Akt pathway strongly support direct activation of Akt via Fc receptors as the anti-apoptotic mechanism behind the immune complex-mediated survival. Moreover, although the neutralizing antibody effectively blocked monocyte survival induced by added M-CSF, the neutralizing anti–M-CSF antibody had no effect on the IC-mediated monocyte survival, demonstrating that the monocyte survival was promoted by a direct, FcR-mediated mechanism, which was independent of the production of M-CSF.
Human monocytes constitutively express Fc receptors I and II, whereas only a subset of monocytes express FcRIII.38 FcRI (CD64) binds monomeric as well as aggregated human IgG with high affinity, whereas FcRII (CD32) and FcRIII (CD16) are receptors of lower affinity that only bind IgG in the form of ICs with a preference for IgG1 and IgG3.39,40 Immunohistochemical analysis has shown the presence of all three classes of FcRs in human atherosclerotic coronary arteries, where the majority of the receptor-bearing cells were of mononuclear phagocyte origin.41 Our present results showed that FcRI, and possibly also FcRII are involved in the OxLDL–IgG IC-mediated monocyte survival. Pre-incubation of monocytes with blocking antibodies against FcRI and II, resulted in a highly significant 68% and a nonsignificant 23% decrease, respectively, in the number of viable cells. Our results, indicating the involvement of FcRI, and possibly also of II, in the OxLDL–IgG IC-induced monocyte survival, are consistent with previous data showing involvement of FcRI and II in uptake of and signaling induced by oxLDL-containing ICs by U936 and THP-1 cell lines and by human monocyte-derived macrophages.13,42,43
The affinity of human antibodies against oxLDL is relatively low, and therefore only soluble ICs are formed, when the antibodies are incubated with oxLDL in vitro. Soluble ICs, in contrast to immobilized ICs or insoluble (large) ICs, poorly cross-link Fc receptors. Consistently with previous data showing reduced signaling with soluble ICs,44 we found that such soluble ICs were not able to induce monocyte survival (Figure 6, columns e and h). However, it is likely that some OxLDL–IgG ICs in atherosclerotic lesions are immobilized, because a fraction of arterial oxLDL is matrix-bound via, e.g., lipoprotein lipase.45 To mimic such arterial immobilized ICs, we used rabbit IgG against human LDL that is able to form insoluble ICs12 and also generated insoluble ICs by bridging the soluble immune complexes containing oxLDL and either human anti-MDA-apoB antibodies or human oxLDL antibodies with F(ab)2 fragments of goat anti-human IgG. The results obtained with these 2 different models of arterial immobilized ICs were similar with regard to monocyte survival (Figure 1B and Figure 6, columns f and i) and accord with previous findings showing that immobilization of human OxLDL–IgG ICs to red blood cells or collagen is able to elicit inflammatory signaling in THP-1 cells.43,46
Taken together, our in vitro work showed that OxLDL–IgG ICs promote monocyte survival by cross-linking Fc receptors with ensuing activation of Akt-dependent survival signaling. This in vitro observation provides novel insights into the pathogenetic role of OxLDL–IgG ICs formed in the atherosclerotic sites of arterial intima. First, the reduction of monocyte apoptosis may be of great importance in atherogenesis, because all the intimal macrophages are derived from blood-borne monocytes, and thus modulation of monocyte survival may affect the genesis and maintenance of intimal macrophage population. Second, the FcR-mediated uptake of OxLDL–IgG ICs may provide a unique mechanism of early transformation of the immigrated monocytes into foam cells at the stage when the scavenger receptor expression is still low.47,48 As immune complexes are activators of complement cascade and complement activation takes place in human atherosclerotic lesions,49 it will be of interest to study the consequence of complement activation on IC-mediated inflammation in the arterial wall.
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Acknowledgments |
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The expert technical assistance of Leena Saikko, Mari Jokinen, and Suvi Mäkinen is gratefully acknowledged. The Wihuri Research Institute is maintained by the Jenny and Antti Wihuri Foundation. This study was also supported by grants from the Aarne Koskelo Foundation (R.O.), and AstraZeneca (R.O.), and the Research and Science Foundation of Farmos (R.O.).
Received July 13, 2005; accepted December 3, 2005.
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