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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1565.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Interferon- Induces Downregulation of Tangier Disease Gene (ATP-Binding-Cassette Transporter 1) in Macrophage-Derived Foam Cells

Constantinos G. Panousis; Steven H. Zuckerman

From the Division of Cardiovascular Research, Lilly Research Labs, Indianapolis, Ind.

Correspondence to Steven H. Zuckerman, Division of Cardiovascular Research, Lilly Research Labs, Indianapolis, IN 46285. E-mail Zuckerman_Steven{at}lilly.com

	Abstract

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Abstract—Cholesterol efflux is a fundamental process that serves to mitigate cholesterol accumulation and macrophage foam cell formation. Recently, we reported that cholesterol efflux to high density lipoprotein subfraction 3 was reduced by interferon- (IFN-) and that this decrease was associated with an increase in acyl coenzyme A:cholesterol acyltransferase (ACAT) expression. In the present study, although treatment of murine peritoneal macrophages with IFN- resulted in a 2-fold decrease in HDL-mediated cholesterol efflux, efflux to lipid-free apolipoprotein A-I was reduced >4-fold and approached basal levels. This decrease was associated with a 3- to 4-fold reduction in ATP-binding-cassette transporter 1 (ABC1) mRNA content, the gene responsible for the defect in Tangier disease. Consistent with the reduction in cholesterol and phospholipid efflux in Tangier fibroblasts, downregulation of ABC1 expression by IFN- also resulted in reduced phosphatidylcholine and sphingomyelin efflux to apolipoprotein A-I. Whereas foam cells had a 3-fold increase in ABC1 mRNA, the decrease in ABC1 message levels by IFN- was observed in foam cells and control macrophages. This effect of IFN- was independent of general macrophage activation (inasmuch as similar changes were not detected with granulocyte-macrophage colony–stimulating factor) and was not observed with other ABC transporters (inasmuch as the expression of the transporter in antigen processing was upregulated 4-fold in these same cells). Therefore, by decreasing cholesterol efflux through pathways that include the upregulation of ACAT and the downregulation of ABC1, IFN- can shift the equilibrium between macrophages and foam cells and thus impact the progression of an atherosclerotic lesion.

Key Words: interferon- • cholesterol efflux • apolipoprotein A-I • ATP-binding-cassette transporter 1

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Cholesterol efflux plays a central role in macrophage cholesterol metabolism.¹ Although cholesterol accumulation is regulated by reductions in de novo cholesterol synthesis and LDL receptor surface expression, macrophages continue to internalize cholesterol in modified LDL via scavenger receptors.^{2 3} The resulting cytoplasmic cholesterol accumulation is reversible after cholesterol efflux to HDL, a first step in "reverse cholesterol transport."⁴

Cholesterol efflux to HDL is believed to be mediated by 2 distinct pathways. In the first, cholesterol moves to acceptor particles through passive diffusion and is facilitated by HDL binding to the type B scavenger receptors SR-BI and CD36.^{5 6 7} The second pathway is an active process and involves the apolipoprotein components of HDL, such as apoA-I and apoE.^{8 9} During this process, lipid-poor apolipoproteins mediate phospholipid and cholesterol efflux, resulting in the formation of pre-ß-HDL–like particles. This second pathway is defective in cells from patients with Tangier disease (TD), a disease that is characterized by severe HDL deficiency and increased macrophage cholesteryl ester accumulation in the tonsils and other lymphoid tissues.^{10 11 12} The gene that is mutated in TD patients was recently demonstrated to be the ATP-binding-cassette transporter 1 (ABC1).^{13 14 15} However, in contrast to the loss of function in TD, ABC1 expression can be upregulated by cholesterol loading or cAMP elevation and result in increased apolipoprotein-mediated cholesterol efflux.^{4 16 17 18}

Recently, we reported that the macrophage-activating factor, interferon- (IFN-), increases the activity and expression of acyl coenzyme A:cholesterol acyltransferase (ACAT) and reduces cholesterol efflux to HDL₃ in macrophage-derived foam cells.¹⁹ The presence of IFN- within atherosclerotic lesions and its role in disease progression have been supported by studies from human atherosclerotic plaque and in the apoE and IFN- receptor double-knockout mouse.^{20 21 22 23} In the present study, we report that the IFN- effect on cholesterol efflux in murine macrophage-derived foam cells was more pronounced when apoA-I served as the cholesterol acceptor species and, furthermore, that this decrease was consistent with the downregulation of ABC1. The decreased expression of ABC1 by IFN- did not reflect a general effect on all ABC transporters because a related transporter associated with antigen presentation, transporter in antigen processing (TAP)-1, did, as expected, demonstrate an increase in message expression.^{24 25} The reduction of HDL₃ and apoA-I–mediated cholesterol efflux further supports a role for IFN- in promoting cholesteryl ester accumulation and foam cell formation within the arterial wall.

	Methods

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Cell Culture
Peritoneal macrophages were obtained from thioglycolate-elicited BALB/c mice by peritoneal lavage and maintained in culture in RPMI 1640 supplemented with 2% FCS (Hyclone Laboratories). Macrophages were converted to foam cells by incubation for 48 hours with 50 µg/mL acetylated LDL (Ac-LDL, Intracel Corp). Cells were washed with PBS and incubated for an additional 48 hours in RPMI 1640 with 1 mg/mL fatty acid–free BSA (Sigma Chemical Co) in the presence or absence of 100 U/mL IFN- (Biosource International) or 10 ng/mL granulocyte-macrophage colony–stimulating factor (GM-CSF, R&D Systems). This concentration of IFN- was determined to maximally inhibit cholesterol efflux. All animal studies were in compliance with institutional guidelines.

Cholesterol Efflux
Peritoneal macrophages were seeded in 24-well plates at 4x10⁵ cells per milliliter and converted to foam cells with Ac-LDL in the presence of 0.4 µCi/mL [¹⁴C]cholesterol (New England Nuclear) for 48 hours. Foam cells were washed with PBS and incubated in the absence or presence of 100 U/mL IFN- in 1 mg/mL BSA and RPMI 1640 for an additional 48 hours. After IFN- treatment, cells were washed with PBS and incubated for 6 hours either with BSA, HDL, or apoA-I (Intracel), and radioactivity was measured in the supernatant and the cell monolayers after lysis with 250 µL of 0.1 NaOH. Cholesterol efflux was expressed as a percentage of counts in the supernatant versus total [¹⁴C]cholesterol counts.

Phospholipid Efflux
Foam cells were induced with IFN- and, during the last 18 hours, incubated with 0.4 µCi/mL of [¹⁴C]choline chloride to label the choline-containing phospholipids, phosphatidylcholine and sphingomyelin. Phospholipid efflux to either medium alone or 10 µg/mL apoA-I was measured at 6 hours. After incubation, cell monolayers were lysed with 0.2% SDS, and supernatants were clarified by centrifugation. Lipids from the cell lysate and the supernatant were first extracted according to the method of Bligh and Dyer²⁶ and separated by thin-layer chromatography with the use of silica G plates developed in chloroform/methanol/ammonia (25% [wt/vol])/water (50:65:5:4 [vol/vol]). Phosphatidylcholine and sphingomyelin spots were visualized by I₂ vapors and identified by comigration with standards. Relative radioactivity was measured by Phosphoscreen and quantified by PhosphorImager (Molecular Dynamics Inc). Phospholipid efflux was expressed as percent counts in the supernatant versus total for each individual lipid.

Northern Blot Analysis
Total RNA followed by 1 round of poly(A)⁺ RNA purification was prepared by using RNA isolation kits (Qiagen). Poly(A)⁺ RNA was resolved on 0.7% formaldehyde agarose gels and transferred to Nytran nylon membranes overnight by using the Turboblotter system (Schleicher and Schuell Inc). Membranes were prehybridized in hybridization buffer and hybridized in fresh buffer with [-³²P]dATP polymerase chain reaction (PCR)-amplified DNA probes labeled with random primers (GIBCO).²⁷ The following sets of primers were used to amplify the following: ABC1, sense (5'-TGGCCAGTCTGTGTAACGGATCAA-3') and antisense (5'-GATGCGGGACACTGCCTGGTAGAT-3'); ACAT1, sense (5'-GGAC-ACATACAGAAATGGTCACAT-3') and antisense (5'-GCACAAA-ACCTAGAACTCCAAGTT-3'); TAP-1, sense (5'-GCTTCAGTTC-ACCCAGGCTGTTCA-3') and antisense (5'-GTCCGGTTCAGG-CCATACGCAATA-3'); and S29, sense (5'-TCTGAAGGCAAGATGG-GTCACCA-3') and antisense (5'-TTTGTGTACAAAGACTAG-CATGAT-3'). Membranes after hybridization were washed in 2x SSC and 1% SDS and exposed to Kodak Biomax-MS film or to Phosphoscreen. Quantification was performed with a PhosphorImager, and normalization was performed relative to the hybridization intensity of the S29 signal.

Statistics
Statistical analysis was performed by Student unpaired (2-tailed) t test. Values are reported as mean±SD. The 95% confidence limit (P<0.05) was taken as significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The macrophage-activating factor IFN- has recently been demonstrated to inhibit cholesterol efflux in macrophage-derived foam cells when HDL₃ was used as the cholesterol acceptor species.¹⁹ These effects were consistent with an increase in ACAT activity and expression. However, to what extent the effects of IFN- on cholesterol efflux involved other processes associated with the intracellular regulation of cholesterol levels was unclear. In the present study, it was observed that the reduction of cholesterol efflux by IFN- was more significant when apoA-I rather than HDL₃ was used as the acceptor species (Figure 1A). Although IFN- treatment resulted in an 2-fold reduction in efflux when HDL₃ or total HDL was used as the acceptor particle, the decrease in efflux was 3- to 4-fold with apoA-I as the acceptor species. The residual efflux observed in IFN-–stimulated foam cells was similar to that detected when the efflux was measured in the absence of cholesterol acceptor species with the use of BSA-supplemented media (Figure 1A). In control cells, the apoA-I–mediated cholesterol efflux was concentration dependent and reached maximum levels at 10 µg/mL (Figure 1B). However, cholesterol efflux in IFN-–stimulated cells remained at basal levels even at apoA-I concentrations up to 40 µg/mL. This inhibition was specific to IFN- and was not related to differences in loading, because control and treated cells had equal amounts of radioactivity (data not shown). The more pronounced reduction in cholesterol efflux mediated by IFN- when apoA-I was used as the acceptor species suggested that regulation of cholesterol efflux by IFN- may occur by apoA-I–dependent pathways.

View larger version (16K): [in this window] [in a new window]   Figure 1. Effects of IFN- on cholesterol efflux in macrophage-derived foam cells. Macrophages were converted to foam cells with 50 µg/mL Ac-LDL in the presence of [14C]cholesterol for 48 hours. After incubation, cells were exposed to RPMI 1640 with 1 mg/mL BSA medium in the absence or presence of 100 U/mL of IFN- for 48 hours. A, Efflux to medium alone, BSA (100 µg/mL), HDL (100 µg/mL), and free apoA-I (50 µg/mL) was measured at 6 hours and expressed as percentage of total [14C]cholesterol. B, Cholesterol efflux was measured by using increasing amounts of apoA-I as the acceptor species. Each value represents the mean±SD of triplicates. *P<0.01 for control vs IFN-–treated cells by 2-tailed unpaired Student t test.

ApoA-I–mediated cholesterol efflux is defective in cells from patients with TD.¹² The gene responsible for this phenotype was recently identified as the ABC1 transporter, and its expression is well correlated with conditions that affect apolipoprotein-mediated cholesterol efflux.^{4 13 14 15 16 17 18} Therefore, Northern blot analysis was performed in control and macrophage-derived foam cells to determine the effect of IFN- stimulation on ABC1 expression. As demonstrated (Figure 2), cholesterol loading in macrophages resulted in a >3-fold induction in ABC1 expression. However, this cholesterol-dependent increase in ABC1 was completely inhibited by IFN- treatment, and even in nonfoam cells, IFN- significantly reduced ABC1 message expression. The magnitude in the reduction of ABC1 expression, between 3- and 4-fold, was consistent with the extent of cholesterol efflux inhibition when apoA-I was used as the acceptor species.

View larger version (28K): [in this window] [in a new window]   Figure 2. ABC1 expression is downregulated by IFN-. A, Macrophages or macrophage-derived foam cells were incubated for 48 hours in the absence or presence of 100 U/mL IFN-. Poly(A)+ RNA was isolated from cells and subjected to Northern blot analysis by use of PCR-labeled probes for ABC1 and S29. B, Quantification of the radiolabeled bands was performed by PhosphorImager, and expression was adjusted to S29 as an internal standard. Brackets indicate the standard deviation of the mean from 3 independent experiments. *P<0.01 vs no IFN- treatment (control) by 2-tailed unpaired Student t test.

To determine whether the downregulation of ABC1 was specific to IFN- and not a general response associated with macrophage activation, Northern blot analysis was performed on control cells or macrophages stimulated with IFN- or GM-CSF. As demonstrated (Figure 3), a 4-fold reduction in ABC1 mRNA levels was detected on IFN- treatment, whereas similar effects were not observed with GM-CSF. To confirm that the effect of IFN- was specific to ABC1 and did not reflect a general decrease in all ABC transporters, the effect of IFN- on TAP-1, a transporter that also belongs to the ABC family, was evaluated. As observed (Figure 3B), the expression of TAP-1 was induced >4-fold, whereas again, no changes were observed with GM-CSF treatment. Finally, and consistent with a previous report from this laboratory, a 75% increase in ACAT1 expression was detected with IFN-, whereas GM-CSF effects did not achieve statistical significance.¹⁹ These results suggest that the inhibition of ABC1 expression is specific to IFN- and that the upregulation of ACAT and the downregulation of ABC1 contribute to the reduction of cholesterol efflux by IFN-.

View larger version (37K): [in this window] [in a new window]   Figure 3. Specificity of effects of IFN- on ABC1 expression. A, Foam cells were incubated for 48 hours in the presence of media alone (control), 100 U/mL IFN-, or 10 ng/mL GM-CSF. Poly(A)+ RNA was isolated, and Northern blot analysis was performed by using PCR-radiolabeled probes. The membrane was hybridized with the ABC1 and S29 probes and subsequently stripped and hybridized with TAP-1 and ACAT-1 probes. B, Radiolabeled bands were quantified by PhosphorImager, and expression was adjusted to S29.

Although the downregulation of ABC1 was associated with a significant reduction in cholesterol efflux, its impact on apoA-I to acquire phospholipid from the plasma membrane was unknown. The defect in lipidation of apoA-I has been suggested to be a major cause of the impaired ability of apoA-I to stimulate cholesterol efflux from Tangier cells.^{12 18} To confirm that this process was also downregulated by IFN-, foam cells were incubated with [¹⁴C]choline chloride to label the choline-containing phospholipids, phosphatidylcholine and sphingomyelin. As demonstrated (Figure 4A), >80% of the label was incorporated into phosphatidylcholine compared with sphingomyelin. IFN- inhibited the synthesis of new phosphatidylcholine and sphingomyelin because less [¹⁴C]choline incorporation was detected with IFN-, an observation also reported in Tangier fibroblasts.¹² Therefore, phospholipid efflux was expressed as the percent radioactivity recovered in the medium versus cells and medium combined. As shown (Figure 4B), IFN- resulted in a >4-fold reduction of apoA-I–mediated phosphatidylcholine and sphingomyelin efflux. Therefore, these data suggest that the downregulation of ABC1 expression by IFN- inhibits the ability of apoA-I to extract phospholipids and cholesterol from macrophage-derived foam cells.

View larger version (20K): [in this window] [in a new window]   Figure 4. Reduction of apoA-I–mediated efflux of radiolabeled phospholipids by IFN-. Foam cells were incubated in the presence or absence of 100 U/mL IFN- for 48 hours, and during the final 18 hours, 0.4 µCi/mL of [14C]choline chloride was added to label the choline-containing phospholipids, phosphatidylcholine (PC) and sphingomyelin (SM). Cells were washed, and after 6 hours of incubation with medium with or without 10 µg/mL apoA-I, lipids were extracted from the medium and the cell monolayer and separated by thin-layer chromatography. Radiolabeled spots corresponding to PC or SM were quantified by PhosphorImager. A, Total counts (x106) for PC and SM are shown. B, ApoA-I–mediated phospholipid efflux was calculated by subtracting the efflux to medium and expressed as the percentage of total cellular and medium phospholipid. For each experimental and control group, the brackets represent the standard deviation of the mean from triplicate cultures. *P<0.05 vs no IFN- treatment (control) by 2-tailed unpaired Student t test.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
IFN- has been demonstrated to be present within human atherosclerotic lesions after the infiltration of CD4⁺ Th1 cells and may contribute to the pathology associated with such lesions. The 2 major cell types that accumulate lipid and convert to foam cells within the atherosclerotic plaque, macrophages and smooth muscle cells (SMCs), express IFN- receptors.^{20 21 28} However, the role of IFN- in atherogenesis remains controversial because IFN- receptor knockout mice crossed with apoE knockout mice showed reduced lesions, whereas immune-deficient RAG-2 knockout mice crossed with apoE knockout mice did not exhibit a comparable effect.^{23 29} IFN- treatment in vitro has been reported to decrease the expression of type A scavenger receptors, LDL receptor–related protein, and lipoprotein lipase in macrophages, suggesting antiatherogenic properties, and yet to stimulate the expression of vascular cell adhesion molecule-1 on endothelial cells, class II major histocompatibility antigens in macrophages and SMCs, and type A scavenger receptors on SMCs, effects consistent with proatherogenic changes.^{30 31 32 33 34 35}

Previous studies from this laboratory¹⁹ have reported that treatment of murine macrophage-derived foam cells with IFN- resulted in a reduction in HDL₃-mediated cholesterol efflux, an increase in ACAT message and activity, and an increase in cholesteryl ester accumulation, with the latter observation also reported by Whitman et al.³⁶ In the present study, macrophage activation by IFN- resulted in a significant decrease in ABC1 mRNA levels. Consistent with this downregulation, apoA-I–mediated efflux of cholesterol- and choline-containing phospholipids was significantly reduced. Furthermore, the downregulation of ABC1 was specific for IFN- and was not a general property of ABC transporters or activated macrophages.

Cholesterol efflux can be mediated by 2 mechanisms, passive diffusion or an active apolipoprotein-dependent process.^{5 6 7 8 9} This latter process is defective in TD, in which the macrophages are characterized by significant intracellular accumulation of lipids and cholesteryl esters.^{10 11} The high degree of ABC1 expression in macrophages is consistent with their ability to efflux cholesterol through an apolipoprotein-mediated pathway compared with other cells, such as SMCs.^{37 38 39 40} However, the exact role that ABC1 plays in this process remains unclear. In a proposed model, ABC1 is a cholesterol and/or phospholipid transporter, similar to MDR2, an ABC transporter that is implicated in the secretion of phospholipid and cholesterol into bile.^{41 42 43} In this model, apoA-I interacts with ABC1 on the cell surface, followed by endocytosis and lipidation of apoA-I with cholesterol and phospholipid to form nascent HDL particles, which are then secreted. These particles can then interact with HDL receptors, such as SR-BI and CD36, and further stimulate cholesterol efflux. Consistent with this model, it has been demonstrated that ABC1 is expressed on the plasma membrane and that cAMP elevation, which increases ABC1 expression, also resulted in the formation of a complex between apoA-I and a cell surface protein with a molecular weight similar to ABC1. Furthermore, a cAMP-inducible receptor has been reported to promote apoA-I–mediated cholesterol efflux after receptor-mediated endocytosis and by resecretion of nascent lipoprotein particles.^{18 44 45} This model would predict a reduction in phospholipid and cholesterol efflux by stimuli that decrease ABC1 expression or by loss of function mutations. The present study supports ABC1 involvement in the lipidation of apoA-I, because a 4-fold reduction in phosphatidylcholine and sphingomyelin efflux was observed in IFN-–stimulated macrophages.

In the present study, treatment of macrophage-derived foam cells with IFN- resulted in a 2-fold reduction in HDL-mediated cholesterol efflux, whereas the apoA-I–mediated efflux was almost completely inhibited. Cholesterol efflux to HDL was almost double that of apoA-I, presumably because HDL is already lipidated and can accept cholesterol by passive diffusion as well as through the ABC1-mediated process. The mechanism that underlies the downregulation of apoA-I–mediated cholesterol efflux by IFN- appears to be due primarily to the significant reduction in ABC1 message. In contrast, the mechanism by which IFN- reduces cholesterol efflux to HDL appears to be multifactorial. Previous studies from this laboratory have demonstrated that IFN- decreases HDL binding and is associated with the downregulation of CD36 (S.H. Zuckerman and C.G. Panousis, unpublished data, 2000). In addition, by increasing ACAT activity and expression, IFN- stimulates cholesterol esterification, thereby reducing the free cholesterol pool available for efflux.¹⁹

ABC1 is upregulated by sterols and during macrophage differentiation. Increases in intracellular cholesterol induce ABC1 message levels, and this effect can be reversed by depletion of the intracellular cholesterol pool through stimulation of cholesterol efflux by HDL₃.¹⁷ Similarly, we observed a >3-fold induction of ABC1 message on the incubation of macrophages with Ac-LDL. The mechanism by which ABC1 regulation is linked to the functional status of the macrophage remains unclear. Although the pathway by which IFN- decreases ABC1 expression is uncertain, its possible linkage to the Janus kinase/signal transducer(s) and activator(s) of transcription (Stat) pathway requires further consideration. IFN- preferentially activates Stat1, and yet Stat1 activity is inhibited by cAMP, an agent that has been reported to induce ABC1 expression.⁴⁶ Future studies will focus on this pathway and its relevance to IFN-–mediated regulation of ABC1 expression. Interestingly and in accordance with the possible role of Stat1 in foam cell formation, Grewal et al⁴⁷ reported a case of 2 siblings without hyperlipidemia but with increased macrophage foam cell formation and clinical evidence of extensive xanthomatosis. These patients had increased expression of the IFN-–induced genes Stat1 and inducible protein-10 compared with their nonaffected siblings, further supporting the importance of IFN- and Stat1 in cholesterol trafficking.

The present study, in agreement with previous work,¹⁹ demonstrates that IFN- inhibits cholesterol efflux in macrophages, a process that is important for the prevention of lipid accumulation and conversion to foam cells. The inhibition appears to affect passive and active cholesterol efflux and is mediated through the downregulation of ABC1 as well as the stimulation of ACAT and increase in the esterified cholesterol pool. Therefore, IFN- has the potential to induce foam cell formation within the atherosclerotic plaque, consistent with its proatherogenic properties. Elucidation and inhibition of the mechanism by which IFN- exerts its effects, and specifically the pathway that downregulates ABC1, could lead to development of therapeutic agents that impact vascular lesion progression without necessarily lowering serum cholesterol levels.

	Acknowledgments

 
The authors would like to thank Dr Glenn Evans for his helpful discussions.

Received February 4, 2000; accepted March 20, 2000.

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