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Cell Biology International (2007) 31, 1456–1461 (Printed in Great Britain)
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Interleukin-10 inhibits the down-regulation of ATP binding cassette transporter A1 by tumour necrosis factor-alpha in THP-1 macrophage-derived foam cells
Chun‑li Mei, Zhi‑jian Chen*, Yu‑hua Liao, Yan‑fu Wang, Hong‑yu Peng and Yu Chen
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie-Fang Avenue, Wuhan, Hubei Province 430022, China

Abstract

It is suggested that cholesterol efflux mediated by ATP binding cassette transporter A1 (ABCA1) plays an important role in anti-atherogenesis. However, the effects of inflammatory cytokines on ABCA1 expression and cholesterol accumulation in foam cells are little known. This study investigates the effects of tumour necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) on ABCA1 expression and cholesterol content in THP-1 macrophage-derived foam cells. ABCA1mRNA and protein levels were determined by RT-PCR and Western blot, respectively. The total cholesterol content in THP-1 macrophage-derived foam cells was detected by the zymochemistry method. Results revealed that TNF-α could increase cholesterol content by down-regulating ABCA1 expression in a time-dependent manner in THP-1 macrophage-derived foam cells, which may contribute to its pro-atherosclerotic effect. In addition IL-10 time-dependently decreased cholesterol accumulation by up-regulating ABCA1 expression and inhibited the down-regulation of ABCA1 by TNF-α in THP-1 macrophage-derived foam cells, which may be one of the mechanisms of IL-10 contributing to its anti-atherosclerotic action.

Keywords: ATP binding cassette transporter A1, Cholesterol content, Tumour necrosis factor-alpha, Interleukin-10, THP-1 macrophage-derived foam cells.

*Corresponding author. Tel./fax: +86 27 8572 7340.

1 Introduction

In past decades, high density lipoprotein (HDL) has been proposed to decrease atherosclerosis mainly by reverse cholesterol transport (RCT), a process by which HDL carries excess cholesterol from peripheral tissues and cells, including foam cells, back to the liver for removal from the body (Von Eckardstein et al., 2001). A major breakthrough in the understanding of the mechanism of RCT came with the discovery of the ATP binding cassette transporter A1 (ABCA1) as the molecular defect in Tangier disease (TD), a rare genetic disease characterised by the accumulation of macrophage foam cells in various tissues, severe HDL deficiency, and prevalent atherosclerosis (Oram, 2000). ABCA1 belongs to the ATP binding cassette (ABC) transporter superfamily. It promotes efflux of free cholesterol and phospholipids from cellular membranes to apolipoprotein A-I (apoA-I) and initiates the formation of nascent HDL particles (Wang, 2003; Brewer et al., 2004). ABCA1 is widely expressed in the liver, kidney, adrenal gland, intestine and central nervous system (CNS) (Lawn et al., 2001). It is also prominent in the macrophage foam cells of atherosclerotic lesions. It has been suggested that cholesterol efflux mediated by ABCA1 plays an important role in anti-atherogenesis. Bone marrow transplantation studies have shown that the over-expression of ABCA1 in macrophage foam cells reduces diet-induced atherosclerosis in different mouse models (Aiello et al., 2002; Singaraja et al., 2002).

Atherosclerosis represents an inflammatory reaction in the arterial wall, initiated by the retention of lipoprotein lipids (Libby, 2002). A range of inflammatory cytokines have been demonstrated to be involved in atherogenesis, some with pro-atherogenic properties while others have anti-atherogenic properties. One of the most noticeable pro-inflammatory cytokines is tumour necrosis factor-alpha (TNF-α), which is active inatherosclerotic plaques (Rus et al., 1991). In vitro and in vivo studies have shown that TNF-α signaling is pro-atherogenic (Rus et al., 1991; Young et al., 2002). In contrast to TNF-α, interleukin-10 (IL-10) has pronounced immunosuppressive and anti-inflammatory effects. IL-10 deficiency aggravated and IL-10 over-expression attenuated experimental atherosclerosis (Potteaux et al., 2004; Namiki et al., 2004; Caligiuri et al., 2003). Rubic and Lorenz (2006) reported that IL-10 attenuated cholesterol accumulation by down-regulating CD36 and up-regulating ABCA1 expression in macrophages, indicating that inflammatory cytokines could regulate macrophage cholesterol homeostasis. However, these observations have provided little insight into understanding the relation between inflammatory cytokines and cholesterol accumulation in foam cells. We investigated the effects of TNF-α and IL-10 on ABCA1 expression and cholesterol content in THP-1 macrophage-derived foam cells.

2 Materials and methods

2.1 Materials

The human monocytes line THP-1 was obtained from Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Trizol reagent and RPMI1640 powder were purchased from Gibco (Grand Island, NY). The RT-PCR kit was purchased from TaKaKa (Beijing, China). RNA extraction materials were from Qiagen Ltd (West Sussex, UK). Western blot consumables were purchased from Invitrogen (Carlsbad, CA, USA). Fetal bovine serum (FBS), bovine serum albumin (BSA), TNF-α, IL-10, apolipoprotein A-I (apoA-I) and all other chemicals were purchased from Sigma (St. Louis, MO, USA). Goat polyclonal anti-ABCA1, and horseradish peroxidase (HRP)-conjugated second antibodies were obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA).

2.2 Low density lipoprotein (LDL) isolation and oxidization

Large amounts of plasma LDL were isolated by a two-step ultracentrifugation as described (Wang et al., 1995). LDL (d=1.006–1.063g/ml) fractions were purified from human plasma obtained from healthy volunteers according to published standard protocols. The preparation was performed in a Beckman L8-M ultracentrifuge 70 Ti rotor at 4°C and densities were adjusted with solid kalium bromated KBr.

The isolated LDL was oxidized with 0.01mM CuSO4 for 24h at 37°C. Ox-LDL was dialyzed in phosphate-buffered saline (PBS) for 24h and stopped with PBS containing 0.5mM EDTA. Ox-LDL was concentrated with polyoxyl 20000 (Scaccini et al., 1994). The purity of isolated LDL and ox-LDL was confirmed by the lipoprotein electrophoresis on an agarose gel. The concentration of ox-LDL was measured by the Bradford assay, sterile filtered (0.45μm) and stored for no longer than 14 days in dark at 4°C before use.

2.3 Cell culture and foam cell model

THP-1 cells were seeded into six-well plates at 1×106cells per well in RPMI1640 medium containing 10% fetal bovine serum (FBS). 20IU/ml penicillin, 20μg/ml streptomycin and maintained at 37°C in an humidified atmosphere of 5% CO2. The cells were differentiated into macrophages by the addition of 100ng/ml phorbol 12-myristate 13-acetate (PMA) for 72h. Macrophages were transformed into foam cells by incubation with the presence or absence of 50μg/ml ox-LDL in serum-free RPMI1640 medium containing 0.3% bovine serum albumin (BSA) for 48h. Electron microscopy was applied to appraise the morphology of cells.

2.4 Electron microscopy

The cells were harvested and then fixed by 3% glutaral for 3h at 4°C. After being washed with 100mM cacodylic acid buffer five times for 4h, the cells were fixed with 1% osmic acid for 30min, washed with 100mM cacodylic acid buffer five times for 2h, and soaked into alcohol (50%, 70%, 80%, 90%) for 10min separately to be dewatered, then into 90% acetone for 10min, and 100% acetone three times for 10min. The cells were saturated in mixed liquor of acetone and extemporized epoxide resin embedding medium with the ratio of 1:1 for 1h, in the 1:3 mixtures for 3h and in embedding medium for 1h. In the end, the cells were embedded in capsules. The imbedding medium was polymerised in thermostat oven at the temperature of 65–70°C overnight, 50-nm extra thin sections were cut out. The sections were soaked in 3% uranyl acetate saturated solution, heated by microwave for 30s, and then washed in PBS buffer. After that, the sections were soaked in lead citrate solution heated by microwave for 20s, and then washed in PBS buffer. Finally, the sections were dried in air for observation by electron microscopy.

2.5 Pre-incubation phase

THP-1 foam cells were washed with PBS, and incubated in serum-free RPMI1640 medium containing 0.3% BSA and in the presence or absence of TNF-α (10ng/ml), IL-10 (10ng/ml), and IL-10 (10ng/ml) plus TNF-α (10ng/ml). No toxicity was detected by cell count. The cells were collected at various times from 0 to 48h for RT-PCR and Western blot.

2.6 RT-PCR for ABCA1mRNA expression

Total RNA was isolated and purified by Trizol reagent kit, according to the manufacturer's protocol. RT-PCRs were carried out in 20μl volumes containing 1μg RNA. The sequences of the sense and antisense primers were summarized in Table 1. RNA was treated with DNase I, reverse transcribed at 95°C for 5min, and amplified for ABCA1 and GAPDH using PCR enzymes and reagents according to the following conditions: denaturation (1min, 94°C), annealing (30s, 60°C for ABCA1; 30s, 55°C for GAPDH), extension (40s, 72°C) 35 cycles for ABCA1 and 30 cycles for GAPDH and then the final annealing step at 72°C for 10min. PCR products were separated on 2% agarose gel containing 1μg/ml ethidium bromide, against 2000bp DNA markers. For quantification, ABCA1mRNA expression was normalized to GAPDH expression.

Table 1.

Primers used in the RT-PCR analysis

PrimerSequenceLength
ABCA1-F5′-ACA ACC AAA CCT CAC ACT ACT G-3′439 bp
ABCA1-R5′-ATA GAT CCC ATT ACA GAC AGC G-3′
GAPDH-F5′-TCA CCA TCT TCC AGG AGC GAG-3′648 bp
GAPDH-R5′-TGT CGC TGT TGA AGT CAG AG-3′

2.7 Western blot for ABCA1 protein level

Cells were washed with pre-cooling PBS, centrifuged at 4°C 3000g for 5min, lysed in ice-cold buffer containing 10mM Hepes (pH 7.4), 10mM KCl, 1.5mM MgCl2, 0.1mM sodium EDTA, 0.1mM sodium EGTA, 1.0mM DTT, 1.0mM PMSF, and 1μg/ml protease inhibitor aprotinin for 30min and centrifuged at 4°C 2000rpm for 10min. The protein concentration in cellular supernatants was determined by the Bradford assay. Equal amounts of protein (60μg) were separated on 6% SDS-polyacrylamide (SDS-PAGE) gels and electrophoretically transferred to nitrocellulose (NC) membrane and blocked 2h (5% ‘degrease milk powder’ in Tween/PBS buffer; vacillating bed; and room temperature). Membranes were incubated with goat polyclonal anti-ABCA1, diluted 1:200 for overnight at 4°C. Membranes were then washed three times (Tween/PBS buffer, 15min) and incubated with horseradish peroxidase (HRP)-conjugated secondary anti-goat, diluted 1:5000 for 1h at room temperature and bands visualized by enhanced chemiluminescence (ECL). Equal protein loading was verified by re-incubating the membrane with an anti-β-actin antibody. For quantification, ABCA1 protein levels were normalized to the β-actin expression.

2.8 Measurement of cellular total cholesterol

The cellular total cholesterol content was measured by zymochemistry method as described (Gamble et al., 1978). After pre-incubation phase at various times from 0 to 48h, the cells were cultured in serum-free RPMI1640 medium with apolipoprotein A-I (apoA-I) for additional 12h, and then washed three times with PBS and transferred to 12×75mm glass tubes. After centrifugation and removal of the medium used for harvesting cells, 0.5ml of 100mmol/L potassium phosphate buffer (pH 7.4) was added to the cell pellet. Each sample was sonified for 1min using the microtip of the sonifier and 0.1ml samples (other samples for assay of protein) were transferred to 12×75mm glass tubes for determination of total cholesterol. The assay buffer containing 100mM potassium phosphate buffer (pH 7.4), 2U/ml cholesterol oxidase, 30U/ml horseradish peroxidase, 0.4U/ml cholesterol ester hydrolase, 1% Triton X-100, 20mM sodium cholate and 4mg/ml p-hydroxyphenylacetic acid was then added. After incubation for 60min at 37°C, fluorescence was measured in HITACHI 650-60 Spectrophotometer (excitation, 325nm; emission, 415nm). The total cholesterol content of foam cells was determined by the standard curve (1–10mg/L standard cholesterol).

2.9 Statistical analysis

The experimental data were expressed as means±SD. Time–response curves were analysed by one-way ANOVA with Dunnett's post-test. Direct comparisons between two groups were made using the Student's t-test; where data from more than two groups were available, repeated measures ANOVA, followed by the Tukey–Kramer's multiple comparison test were used. P-value <0.05 was considered statistically significant.

3 Results

3.1 Formation of THP-1 macrophage-derived foam cells

As shown in Fig. 1, compared with macrophages (Fig. 1A), many lipid-filled vacuoles appeared in the cytoplasm of ox-LDL-treated THP-1 macrophages (Fig. 1B). The results of electron microscopy indicate the formation of THP-1 macrophage-derived foam cells in morphology.

Fig. 1

Formation of THP-1 macrophage-derived foam cells. (A) ox-LDL-untreated THP-1 macrophages were observed by electron microscopy. (B) ox-LDL-treated THP-1 macrophages were observed by electron microscopy. Black arrow indicates lipid-filled vacuoles in cytoplasm. Magnification ×80000.

3.2 Effects of TNF-α and IL-10 on ABCA1 expression in THP-1 macrophage-derived foam cells

RT-PCR revealed that TNF-α time-dependently down-regulated ABCA1mRNA expression in THP-1 macrophage-derived foam cells compared with control group (P<0.01) (Fig. 2A, and C). IL-10 inhibited the down-regulation of ABCA1mRNA expression by TNF-α in a time-dependent manner compared with TNF-α group (P<0.05) (Fig. 2B, and C). However, ABCA1mRNA expression remained below basal levels by 48h. IL-10 also time-dependently up-regulated basal ABCA1mRNA expression compared with control group (P<0.01) (Fig. 2B, and C).

Fig. 2

Effects of TNF-α and IL-10 on ABCA1 expression in THP-1 macrophage-derived foam cells. THP-1 macrophage-derived foam cells were incubated with TNF-α (10ng/ml), IL-10 (10ng/ml), and IL-10 (10ng/ml) plus TNF-α (10ng/ml) for different durations. (A) Total RNA was extracted from control, TNF-α treated THP-1 macrophage-derived foam cells. Products of RT-PCR determined ABCA1mRNA expression. (B) Total RNA was extracted from IL-10, and IL-10 plus TNF-α treated THP-1 macrophage-derived foam cells. Products of RT-PCR determined ABCA1mRNA expression. (C) Line symbols are representative of ABCA1mRNA expression relative to GAPDH in various durations from three independent experiments (n=3, means±SD). **P<0.01 compared with control group and #P<0.05, ##P<0.01 compared with TNF-α group. (D) Products of Western blot determined ABCA1 protein levels. (E) Line symbols are representative of ABCA1 protein level relative to β-actin in various conditions from three independent experiments (n=3, means±SD). *P<0.05, **P<0.01 compared with control group and #P<0.05, ##P<0.01 compared with TNF-α group.

In similar experiments, we investigated the levels of ABCA1 protein, as shown by Western blot as a band of ≈220kDa (Fig. 2D). TNF-α down-regulated ABCA1 protein levels in a time-dependent manner compared with control group (P<0.01) (Fig. 2D, and E). IL-10 inhibited the down-regulation of ABCA1 protein levels by TNF-α in a time-dependent manner (P<0.05) (Fig. 2D, and E). However, ABCA1 protein levels remained below basal levels by 48h. IL-10 also time-dependently up-regulated basal ABCA1 protein levels compared with control group (P<0.01) (Fig. 2D, and E). No signs of cellular apoptosis or necrosis were detected by TUNEL or other assays (data not shown).

3.3 Effects of TNF-α and IL-10 on the total cholesterol content in THP-1 macrophage-derived foam cells

To study the effects of TNF-α and IL-10 on ABCA1-mediated cholesterol efflux, we investigated the total cholesterol content in THP-1 macrophage-derived foam cells (Fig. 3). TNF-α increased the total cholesterol content at 12h and the effect was peaked at 48h in THP-1 macrophage-derived foam cells compared with control group (P<0.01). IL-10 obviously decreased the cellular total cholesterol content after 12h incubation, and reached a minimum at 48h compared with control group (P<0.01). Pre-incubation with IL-10 for 2h attenuated the increment of cholesterol content by TNF-α in a time-dependent manner compared with TNF-α group (P<0.01). However, the cellular total cholesterol content remained above basal levels by 48h.

Fig. 3

Effects of TNF-α and IL-10 on the total cholesterol content in THP-1 macrophage-derived foam cells. THP-1 macrophage-derived foam cells were incubated with TNF-α (10ng/ml), IL-10 (10ng/ml), and IL-10 (10ng/ml) plus TNF-α (10ng/ml) for different durations, and then incubated with apoA-I (10ng/ml) for 12h. The cellular total cholesterol contents were determined by zymochemistry method. Line symbols are representative of the total cholesterol content in various durations from three independent experiments (n=3, means±SD). **P<0.01 compared with control group and ##P<0.01 compared with TNF-α group.

4 Discussion

Both clinical and biochemical evidence strongly suggest that the development of atherosclerotic lesions can be accelerated by local actions of inflammatory cytokines on endothelial cells (Young et al., 2002; Hansson, 2005). TNF-α is a key pro-inflammatory cytokine in the inflammatory process of atherosclerosis. It has been localised in atheromatous plaques, which it is thought to contribute to the development and progression of atherosclerosis by augmenting the local inflammatory response and altering lipid homeostasis (Rus et al., 1991; Napolitano and Bravo, 2005; Vogel et al., 2004). Previous studies have shown that pro-inflammatory cytokines promote lipid accumulation in human mesangial cell by inducing type A scavenger receptor (Francone et al., 2005).

This study has demonstrated that TNF-α inhibits ABCA1mRNA and protein levels in a time-dependent manner in THP-1 macrophage-derived foam cells. On the functional level, the down-regulation of ABCA1 by TNF-α was shown to increase cellular cholesterol accumulation. It provides a plausible mechanism by which TNF-α might impair cellular cholesterol efflux to lipid-free apoA-I by inhibiting ABCA1 expression. Inhibition of the ABCA1 pathway by TNF-α might in part explain the clinical observation that patients with an activated inflammatory response have low circulating levels of HDL in plasma. In fact, the levels of TNF-α are independent predicators of atherosclerotic cardiovascular events in older persons (Skoog et al., 2002). According to the recent data (Panousis and Zuckeman, 2000), the pro-inflammatory lymphokine gamma interferon is capable to down-regulate ABCA1 expression in macrophage-derived foam cells. Thus, our results are similar to previous studies, indicating pro-inflammatory cytokines have new pro-atherosclerotic effect by inhibiting ABCA1 expression and increasing cholesterol accumulation.

Importantly, we demonstrated that anti-inflammatory cytokine IL-10 induced ABCA1 expression and increased cholesterol efflux in a time-dependent manner in THP-1 macrophage-derived foam cells leading to the decrease of cholesterol content of foam cells. Moreover, we observed that the down-regulation of ABCA1 expression by TNF-α was time-dependently inhibited by pre-incubation with IL-10. Meantime, IL-10 also time-dependently attenuated the increment of cellular cholesterol content by TNF-α. These results suggest that IL-10 signaling may have a protective role in preventing cholesterol accumulation and atherogenesis by inducing ABCA1 expression and cholesterol efflux. The negative interaction of the two inflammatory cytokines on ABCA1 and cellular cholesterol content may be in part explained by the inhibition of activation of TNF-α by IL-10. IL-10 is a pleiotropic anti-inflammatory cytokine produced by many cell types including lymphocytes, mass cells and macrophages (Potteaux et al., 2004; Tedgui and Mallat, 2001; Mallat et al., 1999). Clinical trials as well as experimental studies have shown that IL-10 has anti-atherogenic effect (Potteaux et al., 2004; Namiki et al., 2004). Even in animal models such as apolipoprotein E (apoE) or LDL-receptor knockout mice, IL-10 profoundly reduced the lipid accumulation in the vessel wall (Potteaux et al., 2004; Pinderski et al., 2002). However, IL-10 cannot reverse the down-regulation of ABCA1 expression by TNF-α, indicating that inflammatory response cannot be a sole factor in regulating ABCA1 expression. Thus, unknown intermediated factors involved in regulating ABCA1 expression need to be identified further.

Gerbod-Giannone et al. (2006) reported that TNF-α up-regulated ABCA1 expression in macrophage and in phagocytes ingesting apoptotic cells. It is not clear whether the discrepancy is due to different cell types, species specificity or other unknown factors. Although Rubic and Lorenz (2006) reported that IL-10 up-regulated ABCA1 expression by liver X receptor (LXR) pathways in macrophages, the question remains as to the mechanism by which TNF-α and IL-10 regulate ABCA1 expression in foam cells. Nuclear factor-kappa B (NF-κB) is a key nuclear transcription factor, which plays an important role in regulation of a variety of genes involved in the inflammatory response, whose activation has been linked to the onset of atherosclerosis (Brand et al., 1996). TNF-α promoted the activation of NF-κB, while IL-10 inhibited the activation of NF-κB (Van Oostrom et al., 2004; Schottelius et al., 1999). We, therefore, also studied the effects of the activation of NF-κB on ABCA1 expression in THP-1 macrophage-derived foam cells. Our results indicated that the effects of TNF-α and IL-10 on ABCA1 expression and cholesterol accumulation in foam cells could be involved in the activation of NF-κB (data not shown).

In summary, this study provides new insights into the possible role of inflammatory cytokines in atherosclerosis. TNF-α could increase cholesterol accumulation by down-regulating ABCA1 expression in THP-1 macrophage-derived foam cells, which may contribute to its pro-atherosclerotic effect. IL-10 decreased cholesterol overloading by up-regulating ABCA1 expression and inhibited the effects of TNF-α in THP-1 macrophage-derived foam cells, which may be one of the mechanisms of IL-10 contributing to its anti-atherosclerotic action. Considering the critical role of the ABCA1 transporter in the regulation of cholesterol efflux and HDL metabolism, further investigation of the mechanisms underlying the effects of inflammatory cytokines on ABCA1 expression is important for a better understanding of inflammation and atherogenesis. Alternatively, the potential benefits from the anti-inflammatory process in atherosclerosis also deserve further evaluation.

Acknowledgements

The study was supported by Institute of Cardiovascular, Union Hospital, Wuhan, China. We acknowledge the assistance and excellent technical advice provided by Dr. Heping Guo (Institute of Cardiology, Union Hospital, Wuhan, China).

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Received 12 April 2007/10 May 2007; accepted 12 June 2007

doi:10.1016/j.cellbi.2007.06.009
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