© 1995 American Heart Association, Inc.
Articles |
Effects of Platelet-Derived Growth Factor on the Synthesis of Lipoprotein Lipase in Human Monocyte–Derived Macrophages
From the Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Correspondence to Nobuhiro Yamada, Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Hongo, Tokyo, 113, Japan.
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Abstract |
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Abstract Lipoprotein lipase (LPL), which is secreted by the two predominant cell types in atherosclerotic plaque, macrophages and smooth muscle cells, may be involved in atherosclerosis by generating atherogenic remnant lipoproteins. We investigated the effects of platelet-derived growth factor (PDGF)–BB on the synthesis of LPL by human monocyte–derived macrophages. These cells were cultured in the presence of PDGF-BB for 8 days, after which the enzyme activity, mass, and mRNA levels of LPL were determined. The effect of PDGF-BB was time-dependent and dose-dependent at concentrations of 1 to 10 ng/mL. At 10 ng/mL PDGF-BB enhanced twofold to 2.3-fold the secretion of LPL, and a pulse-labeling study with [35S]methionine revealed that 10 ng/mL PDGF-BB significantly increased the synthesis of LPL. Northern blotting analysis showed that the LPL mRNA level increased dose dependently in macrophages treated with PDGF-BB, and 10 ng/mL PDGF-BB enhanced twofold the expression of LPL mRNA. The protein kinase C inhibitor staurosporine suppressed the effect of PDGF-BB on LPL activity. These results indicate that PDGF-BB stimulated transcription of the LPL gene in human monocyte–derived macrophages through protein kinase C activation and resulted in an increased synthesis of LPL. Therefore, we hypothesize that the augmented synthesis of LPL by PDGF-BB modulates atherosclerosis by influencing lipoprotein metabolism in the vascular wall.
Key Words: macrophages • platelet-derived growth factor • lipoprotein lipase
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Introduction |
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Early atherosclerosis is characterized by the presence of monocyte-derived macrophages. Macrophages take up lipoprotein lipids, and when excessive amounts of lipids accumulate intracellularly, these cells appear foamy.1 Such transformed macrophages are implicated as the foam cells observed in atheromatous lesions and produce many proteins, including lipoprotein lipase (LPL).2 3 LPL, which is also produced by smooth muscle cells in atherosclerotic lesions,2 is an enzyme that hydrolyzes the core triglycerides of chylomicrons and VLDL. Zilversmit4 first proposed that LPL plays an important role in atherosclerosis. He hypothesized that hydrolysis of the triglyceride-rich lipoproteins by LPL in the endothelial lining of arteries could lead to the formation of atherogenic remnants, which might be taken up by arterial wall cells, resulting in cholesterol deposition.
Numerous cytokines and growth factors regulate the cellular functions
of the vascular wall, and tumor necrosis factor (TNF), macrophage
colony-stimulating factor (M-CSF), interleukin (IL)-1, and interferon
gamma are known to influence the production of LPL in
macrophages.5 6 7 8 9 Among cytokines and growth factors,
platelet-derived growth factor (PDGF) plays a major role in
atherosclerosis by stimulating the proliferation of vascular smooth
muscle cells.10 In addition to its mitogenic activities,
PDGF stimulates a wide variety of processes including chemotaxis,
activation of intracellular enzymes, phosphatidylinositol turnover and
Ca2+ mobilization, and stimulation of
tyrosine-specific phosphorylation.11 Human PDGF is
composed of homodimers and heterodimers of two polypeptide chains that
are encoded by two distinct genes.12 Three PDGF isoforms,
AA, AB, and BB, have been identified. The mitogenic activities of PDGF
are mediated through its binding to specific, high-affinity surface
receptors that constitute one member of a family of growth factor
receptors that have intrinsic tyrosine kinase activity.13
Two distinct subtypes of PDGF receptors exist, and molecular receptor
cloning has revealed that different genes encode structurally related
and ß receptors with different binding properties.14
During the maturation and differentiation of human monocytes to
macrophages, PDGF-ß receptor mRNA is transcribed, and PDGF-BB may
influence the functions of macrophages by binding to its specific
receptor in the vascular wall.15 PDGF-BB stimulates
thymidine incorporation and inositol-1,4,5-triphosphate production,
suppresses the production of M-CSF in human monocyte–derived
macrophages, and enhances the uptake of acetylated LDL and acyl
coenzyme A–acyltransferase activity.15 In the present
study, we examined the effects of PDGF-BB on the synthesis of LPL by
human monocyte–derived macrophages.
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Methods |
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Materials
Recombinant human PDGF-BB homodimer, human transforming growth factor (TGF)–ß, and human IL-6 were purchased from Genzyme. Recombinant human TNF-
and IL-1ß were donated by Dr M.
Kawakami.16 RPMI-1640 culture medium was purchased from
GIBCO. Culture dishes and plates were obtained from Corning. All other
chemicals were of analytical grade.
Cells
Human monocyte–derived macrophages were prepared by culturing
human monocytes, which were isolated from the peripheral blood of a
normolipidemic healthy donor by using the Ficoll-Hypaque gradient
method.16 The separated mononuclear cells were washed
three times with phosphate-buffered saline. The cells
(2x106 cells/mL) were then placed in fresh medium
containing 10% fetal calf serum (FCS) and were used as
monocyte-derived macrophages after 8 days of culture.
LPL Activity and Mass
The activities of LPL in both the culture medium and cell
homogenate of monocyte-derived macrophages were assayed by the method
of Nilsson-Ehle and Schotz17 as described.18
After the culture medium was collected, cells were sonicated for 15
seconds in 500 µL of 0.05 mol/L NH4Cl buffer (pH 8.5) on
ice. Both medium (150 µL) and cell homogenate were used for the
assay, and the assay mixture was incubated at 37°C for 30 minutes.
Lipase activity was estimated from the amount of free oleic acid that
was released from [3H]triolein during incubation. LPL
enzyme mass was measured by a sandwich enzyme-linked immunosorbent
assay.19 Purified human LPL was used as the standard to
calculate enzyme mass.
Northern Blot Hybridization Analysis
Blot hybridization studies were performed for LPL mRNA of human
monocyte–derived macrophages. Macrophages were treated with 1, 3, or
10 ng/mL PDGF in RPMI-1640 containing 1% FCS after incubation with
serum-free medium for 24 hours. After a 72-hour incubation with
PDGF-BB, total RNA was isolated by the acid guanidine/phenol/chloroform
method.20 Total RNA (10 µg) was fractionated
electrophoretically on a 1% (wt/vol) agarose/2.2 mol/L formaldehyde
gel and transferred to a nylon membrane in 20x SSPE (3.6 mol/L NaCl,
0.2 mol/L Na2HPO4, and 2 mmol/L EDTA, pH
7.7). The membrane was hybridized21 with the cDNA probe
coding for human LPL.22 The filters were washed two times
at room temperature for 15 minutes in 2x SSC (1x SSC: 150 mmol/L NaCl
and 10 mmol/L sodium citrate) and 0.5% (wt/vol) sodium dodecyl sulfate
(SDS) and in 0.2x SSC and 0.5% (wt/vol) SDS at 65°C for 15 minutes
and finally exposed to x-ray film at -80°C.
A run-on assay was performed.23 Macrophages
(1x106 cells/dish) were cultured with 10 ng/mL PDGF
in RPMI-1640 containing 1% FCS for the indicated hours after
incubation with serum-free medium for 24 hours. Cells were collected in
2 mL of 1x SSC by centrifugation at 1000g for 5 minutes,
resuspended in 500 µL homogenization buffer (10 mmol/L Tris-HCl, pH
7.4, containing 10 mmol/L NaCl, 3 mmol/L MgCl2, and
0.5% Nonidet P-40), and then homogenized by gentle agitation. Nuclei
were collected by centrifugation at 1000g for 5 minutes
after incubation on ice for 15 minutes, washed once with homogenization
buffer and once with Nonidet P-40–free buffer, resuspended in 200 µL
of a buffer of 50 mmol/L Tris-HCl, pH 8.3, containing 40% glycerol, 5
mmol/L MgCl2, and 0.1 mmol/L EDTA, and frozen in
liquid nitrogen. Solution (100 µL) containing the nuclei was thawed
for run-on transcription, mixed with 100 µL reaction buffer (10
mmol/L Tris-HCl, pH 8.0, containing 5 mmol/L MgCl2,
300 mmol/L KCl, 0.5 mmol/L each ATP, CTP, and GTP, and 100 µCi
[-32P]UTP [800 Ci/mmol]), and incubated for 30
minutes at 30°C. The reaction mixture was then treated with DNase I
(20 µg/mL) for 10 minutes at 30°C, treated with proteinase K (100
µg/mL) after the addition of 10 mmol/L Tris-HCl, pH 7.4, containing
1% SDS and 5 mmol/L EDTA, and extracted with phenol/chloroform (1:1).
The reaction product (RNA) was rapidly precipitated with 2 mol/L
ammonium acetate and 2 volumes ice-cold ethanol and resuspended in 50
µL Tris buffer (50 mmol/L Tris-HCl, pH 7.5, containing 2 mmol/L
EDTA).
Plasmids (5 µg) containing either human LPL cDNA, human ß-actin
cDNA, or control plasmid (pRc/CMV) were linearized by digestion with
restriction enzymes and treated with 0.2N NaOH at room temperature for
30 minutes. The linearized plasmids were blotted onto Hybond-N membrane
(Amersham), and the membrane was incubated with rapid hybridization
buffer at 65°C for 2 hours and hybridized with
-32P–labeled nuclear RNAs (107 cpm)
isolated from nuclear transcription at 65°C for 2 hours. After
washing, the membrane was exposed to Kodak XAR-5 film at -80°C.
Radiolabeling and Immunoprecipitation
Macrophage monolayers were placed in 2 mL methionine-free medium
in preparation for radiolabeling for a 3-hour period, and the cells
were then labeled metabolically with 200 µCi
[35S]methionine (ICN Biomedical Inc) during incubation
for 5 hours. The radiolabeling was terminated by aspirating the medium.
The cells were washed twice with phosphate-buffered saline and
solubilized in 2 mL of 10 mmol/L phosphate buffer, pH 7.4, containing
0.1% SDS, 0.01% deoxycholate, 0.1% Triton X-100, 0.1% aprotinin,
and 1 mmol/L phenylmethylsulfonyl fluoride. The cell lysate was
centrifuged at 100 000g for 10 minutes. The 900-µL
supernatant was mixed with 10 µL rabbit anti–bovine milk LPL
antiserum19 or 10 µL nonimmune rabbit serum. The
mixtures were incubated for 16 hours at 4°C, mixed with 100
µL Staphylococcus aureus cell suspension (10%, wt/vol;
Bethesda Research Laboratories), and incubated at 4°C for 90
minutes. The immune complexes were recovered by centrifugation at
100 000g for 5 minutes. The pellets were washed three times
with 10 mmol/L phosphate buffer, pH 7.4, containing 0.1% SDS, 0.01%
deoxycholate, and 0.1% Triton X-100, solubilized in 100 µL of 0.1
mol/L Tris-HCl buffer, pH 6.8, containing 3% SDS, 37% glycerol, 33
mmol/L dithiothreitol, and 0.019% bromophenol blue, and then boiled
for 5 minutes. The sample mixtures were centrifuged at
100 000g for 5 minutes, after which the supernatant was
subjected to 12.5% SDS–polyacrylamide gel electrophoresis. The
radiolabeled protein bands were visualized on Kodak XAR-5 x-ray film
after exposure at -80°C. The subunit molecular mass was estimated by
using the following marker proteins: phosphorylase B (94 kD), bovine
serum albumin (68 kD), and ovalbumin (43 kD).
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Results |
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Time-Dependent Effects of PDGF-BB on Secretion of LPL From Monocyte-Derived Macrophages
We cultured macrophages with various concentrations of PDGF-BB. To determine the effects of cell maturation on LPL secretion from monocyte-derived macrophages into the culture medium or in cell lysate, LPL activity was measured at various times and expressed as micromoles free fatty acids per hour assay per milligram total cellular protein. In the absence of PDGF-BB, LPL activity increased constantly thereafter both in the culture medium (Fig 1A
) and cell lysate (Fig 1B). In the presence of 10 ng/mL PDGF-BB, LPL activity in both the
culture medium and cell lysate was enhanced after day 4. This
experiment indicated that at least 2 days were required to upregulate
LPL activity, since LPL activities either in culture medium or cell
lysate on day 2 did not differ between cultures in the presence or
absence of PDGF-BB. The secretion of LPL protein from macrophages into
the culture medium was also enhanced after day 4 in the presence of 10
ng/mL PDGF-BB (Fig 1C).
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In an attempt to study the response kinetics of PDGF-BB in the mature
macrophages, PDGF-BB was added to the culture medium of macrophages
that had been incubated without PDGF-BB for 8 days, after which the
secretion of LPL into medium by monocyte-derived macrophages was
measured at the indicated hours. Stimulation of LPL secretion into the
medium was observed after 24 hours of incubation with 10 ng/mL PDGF-BB
(Fig 2), and the effect was maximal at 48 hours. To
study the mechanism of PDGF-BB effects on LPL secretion, mature
macrophages that had been cultured for 8 days were incubated with
either staurosporine (a protein kinase C inhibitor) or H89 (a
cAMP-dependent kinase inhibitor). Staurosporine inhibited the PDGF
effect, whereas H89 had no significant effect (Table 1).
In the absence of PDGF-BB, staurosporine did not influence LPL activity
secreted by human monocyte–derived macrophages.
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To assess the effects of PDGF-BB on cellular protein, monocytes were cultured with or without 10 ng/mL PDGF-BB for 8 days; cellular protein in the presence and absence of PDGF-BB was 112±34 and 101±15 µg/well (mean±SD of four experiments), respectively, indicating that PDGF-BB had no effect on cellular protein. These biochemical results were consistent with the microscopic observation that the appearance of cells did not change in the presence of PDGF-BB (T.I., unpublished data, 1994).
Dose-Dependent Effects of PDGF-BB on LPL Secretion From
Macrophages
We measured LPL activity in either the culture medium
or cell lysate of macrophages that had been cultured with or
without various concentrations of PDGF-BB for 8 days. The LPL activity
in both the culture medium (Fig 3A) and cell lysate (Fig 3B) was enhanced by incubation with PDGF-BB. The enhancement of LPL
activity in both the culture medium and cell lysate by PDGF-BB was dose
dependent at PDGF-BB concentrations of 1 to 10 ng/mL; the PDGF-BB
effect on LPL activity reached a plateau at 10 ng/mL. The secretion of
LPL protein mass from macrophages was similarly dose dependent in
response to PDGF-BB (Fig 3C).
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Effects of Cytokines on the Secretion of LPL From
Macrophages
In addition to PDGF-BB, several cytokines are available in a
highly pure form that modulate the function and growth of macrophages.
When the effects were compared, M-CSF stimulated LPL secretion
2.9-fold6 (Table 2). Some cytokines, such
as IL-1ß and TGF-ß, showed slightly stimulatory effects on the
secretion of LPL, but the effects were not significant. On the other
hand, TNF- significantly suppressed the secretion of LPL. The
concentrations of the cytokines used for this experiment were
considered to be above those required to exert the maximal effects of
each cytokine.
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Northern Blot Analysis
We examined the mechanism of regulation of LPL by PDGF-BB using
cDNA for human LPL. Two LPL mRNA species of 3.8 and 3.4 kb were
detected in human monocyte–derived macrophages (Fig 4).
Hybridization with a cDNA probe at this position was significantly
increased twofold by 5 and 10 ng/mL PDGF-BB. The similar enhanced
effect of PDGF-BB was observed on apolipoprotein E mRNA level (T.I.,
unpublished observation, 1994). The intensity of the band for LPL mRNA
was estimated by using Fujix BAS 2000. A run-on transcription assay
demonstrated that PDGF-BB stimulated the transcriptional rate of LPL (a
2.1-fold increase at 8 hours; Fig 5), indicating that
LPL synthesis was enhanced by PDGF-BB at the transcriptional level.
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Incorporation of [35S]Methionine by Human
Monocyte–Derived Macrophages
To determine the effect of PDGF-BB on the synthesis of LPL, we
examined the incorporation of [35S]methionine into LPL
protein by macrophages. Macrophages were incubated at 37°C for 3
hours in methionine-free medium and then pulse-labeled with
[35S]methionine for 5 hours after the macrophages were
cultured with or without 10 ng/mL PDGF-BB for 8 days.
Immunoprecipitates were prepared as described above and subjected to
SDS–polyacrylamide gel electrophoresis (Fig 6). A
predominant LPL protein band of 55 to 57 kD was immunoprecipitated from
the cell extract with anti-LPL antibody. The intensity of the band was
increased remarkably by PDGF-BB treatment. This band was not detected
when purified human LPL (20 µg), which was isolated from the medium
of Chinese hamster ovary cells transfected with human LPL
cDNA,24 was added to the immunoprecipitation mixture.
These results from immunoprecipitation studies are consistent with the
cell culture study.
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Discussion |
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Several cell types in atherosclerotic lesions that are monocyte-derived macrophages, smooth muscle cells, endothelial cells, and lymphocytes, are known to secrete cytokines and growth factors. These cytokines and growth factors influence the functions of these cells through action in either the autocrine or paracrine loop.10 25 26 Human monocyte–derived macrophages and macrophage–derived foam cells are also known to secrete LPL,27 and macrophages secrete PDGF-B chain28 in atherosclerotic plaques. Mature human monocyte–derived macrophages constitutively express PDGF-ß receptor,15 and PDGF-ß receptor is expressed in mouse marrow macrophages29 ; thus, PDGF-BB may influence functions of macrophages such as lipoprotein uptake in an autocrine or paracrine manner.
In the present study, we demonstrated that PDGF-BB enhanced the synthesis of LPL in human monocyte–derived macrophages. The results of Northern blot analysis for LPL and run-on assay indicated that PDGF-BB stimulated the synthesis of LPL at the transcriptional level and resulted in the increased secretion of the enzyme into the medium. Neither protein kinase C inhibitor nor cAMP-dependent kinase inhibitor affect the expression of PDGF-ß receptor in mature macrophages15 ; in contrast, protein kinase C inhibitor significantly suppressed the PDGF effect on LPL secretion in mature macrophages. This result indicates that PDGF-BB induced LPL expression through protein kinase C activation.
PDGF may affect LPL secretion directly or through its action on
other factors or cytokines produced by macrophages. Several factors
enhance macrophage LPL expression in vitro. In particular, stimuli of
cell proliferation, such as colony stimulating factors6
and phorbol-12-myristate-13-acetate,8 30 increase LPL
secretion. M-CSF stimulates the synthesis of LPL at the transcriptional
level in both human monocyte–derived macrophages and rat alveolar
macrophages.6 M-CSF also stimulates the proliferation,
differentiation, and maturation of monocyte-macrophage
lineages,31 whereas PDGF stimulates proliferation of
mesenchymal cells.10 11 PDGF-BB has a stimulatory effect
on thymidine incorporation, nuclear labeling with bromouridine, and
IP3 production in mature macrophages,15
results that suggest that PDGF-BB as well as M-CSF is a potent stimuli
for macrophage proliferation, differentiation, and maturation. Thus,
the stimulated synthesis of LPL in response to PDGF-BB may in part
result from macrophage proliferation, differentiation, and maturation.
Maturation of monocytes is essential during the initial 3 days of
culture15 ; in the present experiment, the effect of
PDGF-BB on LPL synthesis was evident from day 4 of culture.
Furthermore, even in mature macrophages that had been cultured for 8
days without PDGF-BB, it took 24 hours to see the effect of PDGF-BB on
LPL secretion into the culture medium (Fig 2
). These time-related
effects of PDGF-BB were similar to those of M-CSF.6
Factors regulating the synthesis of LPL on macrophages as well as
adipose tissue have been studied.5 6 7 8 9 18 30 32 33 34 35 The mode
of regulation of LPL synthesis of macrophages and adipose tissue is not
necessarily the same. For example, insulin enhances the synthesis of
LPL on adipose tissue36 37 but has no effect on the
synthesis of LPL on macrophages.38 39 There may be
tissue-specific regulation in the synthesis of LPL. The effect of M-CSF
on LPL expression is dependent on cell types of macrophages; it is
evident in rat alveolar macrophages and human monocyte–derived
macrophages, but it is minimal in THP-1, P388, and J774
cells.6 We did not find any significant effects of TGF-ß
on LPL secretion, whereas TNF- significantly and IL-6 slightly
inhibited it. The effect of TNF is controversial. White et
al32 report no effect of TNF on LPL expression in
mature human monocyte–derived macrophages, but TNF inhibits LPL in
mouse peritoneal macrophages.7 We incubated human
monocytes with TNF from the beginning of culture, and the results
indicated that the effect of TNF is dependent on the stage of monocyte
maturation and differentiation and on cell types. Similarly, IL-1
inhibits LPL when added to freshly plated cultures but not when added
to mature cultures.5 PDGF-BB stimulated LPL secretion both
when added at the beginning of culture and to mature macrophages.
The major role of LPL is to hydrolyze plasma triglyceride and facilitate the uptake of free fatty acids released after hydrolysis in tissue, such as adipose tissue, muscle, and heart; however, the physiological role of LPL secreted from macrophages is not well understood. The modulation of VLDL by treatment with LPL enhances the uptake through the receptor and causes the accumulation of cholesteryl ester.24 40 41 In addition, LPL-modified LDL is readily taken up by cultured macrophages,42 and LPL facilitates the cellular uptake of lipoproteins containing apolipoprotein B-100 through the interaction with cell-surface heparan sulfate.43 44 45 In the present study, we demonstrated that PDGF enhanced the synthesis of LPL in human monocyte–derived macrophages. We hypothesize that the secreted LPL generates atherogenic remnant lipoproteins by hydrolyzing triglyceride-rich lipoproteins.4
An early event in the development of atherosclerosis is the accumulation of lipid-loaded foam cells in the subendothelial space. Recent evidence suggests that the foam cells are derived from macrophages that have been originated from the circulating monocytes.1 Therefore, the enhanced expression of LPL in response to PDGF may accelerate foam cell formation in atherosclerotic lesions by generating atherogenic remnants. PDGF enhances both cellular uptake of acetylated LDL and the accumulation of cholesteryl ester in human monocyte–derived macrophages.15 Taken together, these findings suggest that PDGF may influence the process of atherosclerosis by regulating the functions of macrophages in the vascular wall, such as LPL-mediated uptake of lipoproteins.
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Acknowledgments |
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This work was supported by a grant from Ono Pharmaceutical Co.
Received November 16, 1994; accepted February 2, 1995.
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