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(Journal of Leukocyte Biology. 2002;71:981-986.)
© 2002 by Society for Leukocyte Biology

Eicosapentaenoic acid inhibits CSF-induced human monocyte survival and maturation into macrophage through the stimulation of H2O2 production

Sachiyo Terada*, Mari Takizawa{dagger}, Shigeru Yamamoto{ddagger}, Osamu Ezaki*, Hiroshige Itakura* and Kiyoko S. Akagawa§

* Division of Clinical Nutrition, National Institute of Health and Nutrition, Tokyo, Japan;
{ddagger} Department of Nutrition, School of Medicine, University of Tokushima, Japan; and
{dagger} AIDS Research Center and
§ Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan

Correspondence: Dr. Kiyoko S. Akagawa, Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. E-mail: akagawak{at}nih.go.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Human studies suggest a beneficial effect of eicosapentaenoic acid (EPA)-supplemented diets on atherosclerotic and atherothrombotic disorders as well as autoimmune and inflammatory diseases and tumors. The effects of EPA on human monocyte survival and maturation into macrophage are not yet known. We studied the effects of EPA on the survival and development into macrophage of human monocyte treated with colony-stimulating factor (CSF). We have found that EPA induces cell death of the monocyte via apoptosis, even in the presence of M-CSF or GM-CSF, and inhibits differentiation from the monocyte to macrophage by inducing H2O2 production. In contrast to the effect of EPA on monocytes, EPA did not induce cell death of monocyte-derived macrophages. Such an apoptosis inducing effect on monocytes by EPA may contribute to the efficacy of EPA in atherosclerosis and autoimmune diseases.

Key Words: apoptosis • cell-surface antigens • atherosclerosis • autoimmune disease


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The macrophage is present at all stages of atherogenesis. The normal role of the macrophage is to act not only as an antigen-presenting cell (APC) to T lymphocytes, but also as a scavenger cell to remove noxious materials and as a source of growth-regulatory molecules and cytokines. Thus, the macrophage is the principal, inflammatory mediator of cells in the atheromatous plaque microenvironment. Human studies suggest a beneficial effect of fish oil-supplemented diets on atherosclerotic and atherothrombotic disorders as well as autoimmune and inflammatory diseases [1 2 3 4 5 6 ] and tumors [7 8 9 10 11 ]. The beneficial effects of fish oil are attributed to its high content of n-3 polyunsaturated fatty acids (PUFAs), particularly in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Reports demonstrate that dietary fish oil, rich in n-3 PUFAs, can alter the membrane composition of human white blood cells, increasing the membrane phospholipid concentrations of EPA and DHA [12 ]. Changes in the membrane fatty acids composition can result in significant alterations in the activity of cells involved in the immune system [13 ]. Several in vivo or in vitro dietary supplementation studies have been performed to elucidate the mechanism of the immunosuppressive effect of n-3 PUFAs [14 ]. Concerning their effect on monocyte/macrophage cells, the n-3 PUFAs have been shown to decrease monocyte chemotaxis [15 ], superoxide generation [16 , 17 ], interleukin (IL)-1, and tumor necrosis factor {alpha} (TNF-{alpha}) production [18 19 20 21 ] and to modify eicosanoid production [22 ]. Treatment of monocytes with EPA [23 24 25 26 ] or a dietary supplementation of EPA suppresses the expression of human leukocyte antigen (HLA)-DR and CD54 on the surface of human monocytes. These molecules play important roles in T cell activation. Thus, n-3 PUFAs influence monocyte/macrophage inflammatory and immune reactions, which are involved in the development of disease.

Previously, we and others [27 28 29 ] showed that colony-stimulating factors (CSF) such as macrophage (M)-CSF and granulocyte macrophage (GM)-CSF stimulate the survival of monocytes and their maturation into macrophages in vitro. In the present study, we examined the effects of highly purified EPA on CSF-induced human monocyte survival. We found that EPA induces monocyte apoptosis and inhibits the generation of mature macrophages through the stimulation of H2O2 production. Furthermore, we show that in contrast to the effect of EPA on monocytes, EPA does not stimulate the cell death of monocyte-derived macrophages.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Reagents
Recombinant human (rh)GM-CSF and rhM-CSF were kindly provided by Schering-Plough Japan (Osaka, Japan) and Morinaga Milk Industry Co., Ltd. (Tokyo, Japan), respectively. The superoxide anion quencher superoxide dismutase (SOD) was purchased from Sigma Chemical Co. (Poole, UK). The hydroxyl and H2O2 quencher human erythrocyte catalase was purchased from Calbiochem-Nova Biochem Co. (La Jolla, CA). EPA was obtained from Sigma Chemical Co. (Poole, UK) and was solubilized in 99% ethanol. The stock solution of EPA (conc. 150 mM) was stored at -20°C under nitrogen until immediately prior to use and was added to the culture media after dilution with culture medium to a final concentration of 75 µM.

Medium
RPMI-1640 medium (Nissui Pharmaceutical Co., Ltd., Tokyo, Japan) was supplemented with 10% heat-inactivated fetal calf serum (FCS; Z. L. Bocknec Laboratories Inc., Ontario, Canada), 2 mM/L-glutamine, 100 µg/ml streptomycin, and 100 U/ml penicillin. The FCS we used contained 0.003 ng lipopolysaccharide (LPS)/ml as measured by the Limullus amebocyte lysate test.

Preparation and culture of human monocytes
Peripheral blood mononuclear cells (PBMC) and monocytes were obtained from venous blood drawn from normal, healthy volunteers as described previously [28 , 30 ]. PBMC were isolated by centrifugation on a Ficoll-Paque density gradient (Lymphoprep; Nycomed, Oslo, Norway) and then were suspended in medium. Monocytes were obtained using a magnetic cell sorter (MACS; Miltenyi Biotec GmbH, Bergisch Gladbach, Germany). PBMC were incubated with anti-CD14 monoclonal antibody-coated microbeads, and the monocytes were isolated by passing the PBMC through MACS with column type LS according to the manufacturer’s instructions. More than 97% of the recovered cells appeared to be monocytes as judged by their morphology, nonspecific esterase staining (cells were stained using a kit for a-naphthyl butyrate esterase), CD14 positivity, and ability to phagocyte latex particles. Monocytes (1.3x105/well in 500 µl) were cultured with M-CSF (104 U/ml), GM-CSF (500 U/ml), or medium alone in the presence or absence of various concentrations of EPA for 7 days in 24-well tissue-culture plates (Falcon No. 3047; Becton Dickinson Labware, Lincoln, Park, NJ).

Assessment of cell numbers and viability
The nonadherent cell number was counted with a hemocytometer, and the viability was assessed by the trypan blue-dye exclusion test. The number of adherent monocytes or monocyte-derived macrophages was determined with the method described previously by Nakagawara and Nathan [31 ]. Briefly, cultures were depleted of medium by gentle aspiration and were replenished with 50–200 µl 1% cetyltrimethyl ammonium bromide (Cetavol; Wako Pure Chemical Industries, Ltd., Osaka, Japan) in 0.1 M citric acid with 0.05% naphthol blue black (Sigma Chemical Co., St. Louis, MO) at room temperature for 3 min. This treatment readily lysed the adherent cells and liberated the stained, intact nuclei, which were then counted using a TATAI hemocytometer (American Optical, Southbridge, MA).

Assessment of apoptosis
Monocytes were cultured for 24 h with M-CSF, GM-CSF, or medium alone in the presence or absence of EPA (75 µM). Apoptosis of cells was assayed by detection of phosphatidylserine on the surface and DNA fragmentation. Detection of phosphatidylserine was performed by the Annexin V staining method using an apoptosis detection kit (R&D Systems, Inc., Minneapolis, MN) and was analyzed by flow cytometry. To detect DNA fragmentation in individual cells, the TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling) method was carried out using an apoptosis detection kit (Genzyme, Cambridge, MA) according to the manufacturer’s specifications, and was analyzed by flow cytometry.

Assay for H2O2 production
The release of H2O2 was detected using the semi-automated microassay demonstrated by De la Harpe and Nathan [32 ]. In brief, 100 µl monocytes (2x105 cells/ml) in the assay mixture containing 30 µM scopoletin (Sigma Chemical Co., St. Louis, MO), 1 mM NaN3, and 1 purpurogallin unit/mL horseradish peroxidase (Sigma Chemical Co.) in Krebs-Ringer phosphate buffer with 5.5 mM glucose were dispensed into 96-well flat-bottom tissue-culture plates (Falcon No. 3072; Becton Dickinson Labware). Immediately after the addition of EPA (final conc. of 75 µM or 150 µM), the culture plates were placed in a fluorometer (Titertek Fluoroskan II; Flow Laboratories Inc., McLean, VA), and the fluorescence was recorded for each well. To monitor the rate of H2O2 release, the fluorescence was recorded from 0 to 180 min at 30-min intervals. H2O2 release was calculated from the loss of fluorescence using the formula: nmol H2O2 released = [(E0-W)/(C0-W)-(Em-W)/(Cm-W)] x S, where E0 is the initial fluorescence reading for the well; Em is the fluorescence reading at the indicated minutes; W is the fluorescence recorded in an empty well; C0 and Cm are the mean fluorescence reading in the cell-free control wells at 0 and indicated minutes (m), respectively; and S is the amount of scopoletin (3 n moles) added to each well at the start of the assay.

Statistical analysis
The significance of all assays was assessed by Student’s t-test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effect of EPA on CSF-induced monocyte survival and development into macrophage
To determine whether EPA affects the CSF-induced monocyte survival and development into macrophages, monocytes were cultured for 8 days with GM-CSF (500 U/ml), M-CSF (104 U/ml), or medium alone in the presence or absence of various concentrations of EPA. Monocytes cultured in GM-CSF or M-CSF alone survived and developed into adherent macrophages, no significant cell death was observed during the culture, and the number of cells recovered was almost the same as that of plated cells as shown previously [27 , 30 ]. EPA alone did not stimulate the monocyte survival or its development into macrophages as well as in cells cultured with medium alone (unpublished results).

Addition of EPA at 0 and 72 h after the start of the culture inhibited the effects of monocytes stimulated with M-CSF or GM-CSF and induced the cell death of monocytes, although the addition of EPA at 72 h was less effective compared with the addition at 0 h (Fig. 1 ). The inhibitory effect of EPA on GM-CSF- or M-CSF-induced monocyte survival and macrophage development was dose dependent, and maximal inhibition was observed with 150 µM EPA (P<0.01; Fig. 1 ). In contrast, addition of EPA at 144 h did not induce cell death even when a higher amount of EPA (150 µM) was added, and in fact, a similar number of viable cells were recovered as in the culture with GM-CSF or M-CSF alone (Fig. 1) . Monocytes cultured in M-CSF or GM-CSF for 144 h had already completed their maturation into macrophages, and these monocytes underwent morphologic changes characteristic of monocyte-to-macrophage maturation such as an increase in size and adherence. The diluent, 0.05% of ethanol, contained in the diluted stock solution in 300 µM EPA, had no effect in this system (unpublished results). These results suggest that EPA stimulate the cell death of monocyte but not of monocyte-derived macrophage.



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  		Figure 1. Effect of EPA on CSF-induced monocyte survival and development into macrophages. Monocytes (1x105) were cultured with GM-CSF (500 U/ml) or M-CSF (10 U/ml), and various concentrations of EPA were added at indicated time points after the start of the culture. The cells were incubated for a total of 8 days. Cell cultures incubated without EPA were used as the controls, and their viability was 100%. Error bars indicate SD. *, P < 0.05; ***, P < 0.005 compared with control.

 
EPA stimulates apoptosis of monocytes
To determine whether the death of monocyte induced by EPA was a result of apoptosis, monocytes were cultured for 24 h with GM-CSF or M-CSF in the presence or absence of EPA (75 µM) and then were stained with Annexin V before being analyzed by fluorescein-activated cell sorter. Annexin V-positive cells in monocytes cultured with GM-CSF + EPA, M-CSF + EPA, and EPA alone were 62%, 60%, and 66%, respectively, whereas for monocytes cultured in GM-CSF, M-CSF, and medium alone, the numbers were 16%, 13%, and 13%, respectively (Fig. 2 ). EPA-induced apoptosis of the monocytes was confirmed further by the detection of cellular DNA fragmentation using the TUNEL method; 30.3% and 14.5% of monocytes cultured in GM-CSF + EPA or M-CSF + EPA were stained with the TUNEL method, and only 1.69% and 1.3% of monocytes cultured in GM-CSF and M-CSF alone were stained, respectively. These results indicate that the cell death induced by EPA is a result of apoptosis.



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  		Figure 2. Flow cytometric analysis of apoptosis in monocytes stimulated with EPA measured by Annexin V staining. Monocytes were cultured for 24 h with M-CSF (104 U/ml), GM-CSF (500 U/ml), or medium alone in the presence or absence of EPA (75 µM) before being stained with Annexin V and assayed by flow cytometry.

 
EPA stimulates H2O2 production from monocyte
Early studies demonstrated that the tumor growth-inhibiting effect of PUFA including EPA depends on free radical generation [11 , 33 , 34 ]. We therefore expected that EPA would enhance the generation of free radicals [reactive oxygen intermediates (ROI)] from monocytes and stimulate the apoptosis. To determine this possibility, we examined the effects of antioxidants on the EPA-stimulated cell death of monocytes. Addition of catalase (500 U/ml) but not SOD (500 U/ml) inhibited the cell death of monocytes cultured in M-CSF + EPA (Fig. 3A ). Addition of catalase to monocytes cultured in GM-CSF + EPA also inhibited the cell death (unpublished results). These results suggest that H2O2 plays an important role in EPA-stimulated apoptosis of the monocyte.



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  		Figure 3. Effects of catalase and SOD on the EPA-induced cell death of monocytes and EPA-stimulated H2O2 production from monocytes. (A) Monocytes (1x105/well/0.5 ml) were cultured with M-CSF (104 U/ml) first bar (lightly hatched) or M-CSF + EPA (75 µM) in the presence of absence of catalase (cata; 500 U/ml) and SOD (500 U/ml) for 7 days. Error bar indicates SD. *, P < 0.05 compared with M-CSF + EPA (75 µM). (B) Monocytes were cultured with M-CSF (104 U/ml) in the presence or absence of EPA (75 µM or 150 µM). The cell number at the time of EPA addition (day=0) was 1 x 105/well. H2O2 production was assayed at the time points indicated. Error bars indicate SD. *, P < 0.05; ***, P < 0.005 compared with control.

 
To verify whether H2O2 is indeed the mediator of EPA-induced monocyte apoptosis, we examined the ability of EPA to stimulate the release of H2O2 from monocytes. As shown in Figure 3B , monocytes cultured in M-CSF alone did not release significant amounts of H2O2 during the incubation time (0–180 min). However, monocytes cultured in M-CSF + EPA released H2O2 in a time- and dose-dependent manner. Monocytes stimulated with 75 µM EPA for 120 min produced significant amounts of H2O2, and maximal production was observed 180 min after stimulation with 150 µM EPA (P<0.05). These results suggest that the apoptosis caused by EPA can be ascribed to the increased H2O2 production from monocytes.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
It is known that the monocyte is a short-lived cell, and in vitro culture of the human monocyte stimulates apoptosis [28 , 30 ]. Lack of serum or low serum supplementation increases and strengthens the induction of apoptosis. In contrast, the addition of a growth factor such as M-CSF or GM-CSF markedly abrogates the apoptosis and stimulates the differentiation of the monocyte into a macrophage [28 29 30 ]. Proinflammatory mediators such as IL-1 or TNF-{alpha} as well as LPS are also known to prevent apoptosis [35 ]. In this study, we have found that EPA induces cell death of the monocyte via apoptosis even in the presence of M-CSF or GM-CSF. Um et al. [36 ] demonstrated that the Fas/FasL system stimulates apoptosis of the monocyte, particularly in monocytes activated with IL-1 or TNF-{alpha} and showed that ROI play a central role as downstream mediators of Fas-induced monocyte apoptosis. We have found that the apoptosis of monocytes induced by EPA is caused by H2O2 released from the monocyte, because the antioxidant catalase rescued the cells successfully and inhibited the EPA-stimulated release of H2O2 from monocytes. Finstad et al. [37 ] has demonstrated a similar cytotoxic effect of EPA on a monocytic cell line (U937 cells): they showed that EPA stimulates the apoptosis of U937 cells and inhibits the macrophage differentiation. In contrast to our study, antioxidants did not rescue the U937 cells from apoptosis induced by EPA. The difference between their study and ours may depend on differences in the cultured cell line and freshly prepared peripheral monocytes. The critical role of ROI is shown to be in the growth inhibitory effect of PUFAs including EPA against various tumor cells [11 , 33 , 34 ]. Li et al. [38 ] also showed that EPA stimulate oxygen radical generation from neutrophils.

In this study, we demonstrated that in contrast to monocytes, the monocyte-derived macrophages are resistant to the cell death-inducing effect of EPA. However, in our preliminary study, the expression of HLA-DR and CD54 on M-M{phi} and CD54 on GM-M{phi} decreased after treatment with EPA for 48 h. Expression of HLA-DR on GM-M{phi} did not change significantly by EPA treatment. However, interferon-{gamma} production by CD4+ T cells from purified protein derivative of tuberclin positive donor was markedly inhibited when EPA-pretreated GM-M{phi} was used as APC. These preliminary findings suggest that monocyte-derived macrophages are still responsive to EPA. A similar down-regulation of APC function and the expression of major histocompatibility complex-class II antigens and CD54 on human and rodent monocyte/macrophage and endothelial cells by EPA have been demonstrated previously [39 40 41 42 43 ]. Thus, failure of EPA to induce cell death in the monocyte-derived macrophage is not a result of a lack of ability to respond to EPA. At present, we do not know the reason why EPA acts differently on monocytes and macrophages. It is generally known, however, that macrophages show pronounced resistance against toxins and stimuli able to evoke apoptosis of monocytes in vitro [44 45 46 ].

PUFAs including EPA are known to activate protein kinase C (PKC) and the peroxisome-proliferator-activated receptor (PPAR) [47 48 49 50 51 ]. The ability of EPA to stimulate monocyte apoptosis and to suppress antigen expression on the monocyte-derived macrophages and APC activity of the cells may be related to the EPA stimulation of PKC and PPAR. Further studies are needed to clarify the mechanisms involved in the EPA suppression.


   ACKNOWLEDGEMENTS
 
This work was supported in part by grants from the Japan Health Science Foundation and Ministry of Health and Welfare of Japan.

Received November 27, 2000; revised January 12, 2002; accepted January 14, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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