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© 1999 American Heart Association, Inc.
Original Contributions |
Dietary 
-3, -6, and -9 Unsaturated Fatty Acids and Growth Factor and Cytokine Gene Expression in Unstimulated and Stimulated Monocytes
A Randomized Volunteer Study
From Medizinische Klinik, Klinikum Innenstadt, University of Munich, Munich, Germany.
Correspondence to Clemens von Schacky, MD, Medizinische Klinik, Klinikum Innenstadt, Universität München, Ziemssenstr 1, D-80336 Munich, Munich, Germany. E-mail vonschacky{at}medinn.med.uni-muenchen.de
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Abstract |
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Abstract—Dietary
-3
fatty acids retard coronary atherosclerosis.
Previously, we demonstrated that dietary -3 fatty acids reduce
platelet-derived growth factor (PDGF)-A and PDGF-B mRNA levels in
unstimulated, human mononuclear cells (MNCs). In a randomized,
investigator-blinded intervention trial, we have now compared the
effect of ingestion of 7 g/d -3, -6, or -9 fatty acids for 4
weeks versus no dietary intervention on PDGF-A, PDGF-B, heparin-bound
epidermal growth factor (HB-EGF), monocyte chemoattractant protein-1
(MCP-1), and interleukin-10 gene expression in unstimulated MNCs and in
monocytes that were adherence-activated ex vivo in a total of
28 volunteers. In unstimulated MNCs, mRNA steady-state levels of
PDGF-A, PDGF-B, and MCP-1 were reduced by 25±10%, 31±13%, and
40±14%, respectively, after -3 fatty acid ingestion, as assessed
by quantitative polymerase chain reaction (all P<0.05).
In monocytes that were adherence-activated ex vivo for 4 and 20
hours, mRNA steady-state levels of PDGF-A, PDGF-B, and MCP-1 were
reduced by 25±13%, 20±15%, and 30±8%, respectively (all
P<0.05). Interleukin-10 and HB-EGF mRNA steady-state
levels were not influenced by -3 fatty acid ingestion. Expression of
all respective mRNAs in control volunteers or in those ingesting -6
or -9 fatty acids were not altered. We conclude that human gene
expression for PDGF-A, PDGF-B, and MCP-1, factors thought relevant to
atherosclerosis, is constitutive, is constant, and can
be reduced only by dietary -3 fatty acids in unstimulated and
adherence-activated monocytes.
Key Words: mRNA • platelet-derived growth factor • monocyte chemoattractant protein-1 • interleukin-10 • heparin-bound epidermal growth factor
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Introduction |
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Ingestion of fish or fish oil rich in the 2
-3 fatty
acids eicosapentaenoic and docosahexaenoic
acids lowers mortality in patients after a myocardial
infarction.1 Although this may partly be due to
reductions in fatal arrhythmias,2 we
recently demonstrated that dietary -3 fatty acids have a beneficial
effect on the course of coronary
atherosclerosis, as assessed by the coronary
angiogram.3 Various mechanisms of action have
been described for dietary -3 fatty acids.4 5 6
One of them, reduced platelet-derived growth factor (PDGF)-A and
PDGF-B mRNA steady-state levels in unstimulated, human mononuclear
cells (MNCs) after ingestion of dietary -3 fatty
acids,7 demonstrated that human gene expression
can be influenced by dietary components. Monocytes/macrophages play a pivotal role in atherosclerotic plaque formation.8 9 Monocytes and macrophages have been shown to synthesize and secrete a series of cytokines and growth factors influencing the atherosclerotic process at the site of a vascular lesion.8 9 10 11 12 13 Among the factors induced and secreted by monocytes/macrophages by a stimulus, like adherence, are PDGF-A, PDGF-B, heparin-bound epidermal growth factor (HB-EGF), monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-10.9 10 12 13 14 15 IL-10 is a cytokine synthesis inhibitor.16 PDGF and HB-EGF are potent mitogens for smooth muscle cell proliferation.8 17 MCP-1 is an attractor and activator of monocytes.12 Both MCP-1 and PDGF are currently thought to be intimately involved in the pathogenesis of atherosclerosis.8 9 18
It is currently unknown whether human gene expression for PDGF-A and
PDGF-B can be reduced by other dietary unsaturated fatty acids, such as
-6 or -9 fatty acids, or is reduced solely and specifically by
-3 fatty acids. It is also unknown whether this reduction persists
after mild monocyte stimulation by adherence ex vivo. Therefore, we
conducted a randomized, investigator-blinded volunteer trial to
evaluate the effects of dietary -3, -6, and -9 fatty acids on
PDGF-A, PDGF-B, MCP-1, HB-EGF, and IL-10 gene expression in human
MNCs.
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Methods |
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Volunteer Study
Male volunteers (n=28, 20 to 38 years of age) who were judged healthy by medical history, routine clinical examination, and normal laboratory screening values were recruited for this study. Written, informed consent was obtained, and volunteers were randomized to supplement their usual diet with seven 1-g capsules per day containing either
-3 fatty acids (fish oil based;
eicosapentaenoic acid 41.4%, docosahexaenoic
acid 23.6%, total saturated fatty acids 0%, no -9 fatty acids, and
total -6 fatty acids 3.9%), -6 fatty acids (corn oil based;
linoleic acid 50.1%, total saturated fatty acids 12.9%, and total
-3 fatty acids 0.6%), or -9 fatty acids (olive oil based; oleic
acid 60.5%, total saturated fatty acids 13.7%, and total -3 fatty
acids 0.6%), all in the form of ethyl esters for 4 weeks. All
formulations were kindly provided by the Biomedical Test Materials
Program of the US Department of Commerce, National Oceanic and
Atmospheric Administration/National Marine Fisheries Services,
Charleston, SC. Thus, 7 volunteers supplemented their diet with -3,
7 with -6, and 7 with -9 fatty acids, while 7 volunteers served
as controls. Blood samples were taken at the onset of the study and on
the day after the 4-week intervention ended. Serum
parameters were measured in an automated Hitachi 917 or 717
serum analyzer. Investigators involved in the analyses
of the study were blinded with respect to randomization of the
volunteers. The study was approved by the Ethics Committee of the
Faculty of Medicine of the Ludwig Maximilians-Universität,
Munich, Germany.
Preparation of Human MNCs
Platelet-free human peripheral MNCs were
isolated from healthy, male volunteers after an overnight fast as
described earlier.7 11 19 20 In brief,
peripheral venous blood was obtained by a free-flow
technique and anticoagulated with acid-citrate-dextrose. After dextran
sedimentation, MNCs were enriched by density
centrifugation through Ficoll-Hypaque 1.077 (Sigma).
Our cell preparation results in unstimulated MNCs, as evidenced by very
low levels of IL-1ß measured by
radioimmunoassay.7 11 19 20 The cell composition
of MNCs was determined by light-microscopic analysis of
May-Grünwald/Giemsa–stained smears. Typically, the mononuclear
fraction contained, on average, 60% monocytes, 35% lymphocytes, <5%
granulocytes, and no platelets.7 11 19 20
Eight cell preparations for the current study contained, on average,
61.8% monocytes, 33.2% lymphocytes, <5% granulocytes, and no
platelets. The absence of platelets was further verified by
checks for EGF mRNA, a specific platelet
marker.19 MNCs (2x106)
were taken for analyses of unstimulated MNCs.
Cell Culture
Freshly isolated MNCs (2x106) were
resuspended in "autologous medium," which consisted of phenol
red–free Dulbecco's modified Eagle's medium (Gibco-BRL) supplemented
with 5% serum prepared from coagulated venous blood (1 hour, 37°C)
of the respective donor at the respective time point, 1% glutamine
(Gibco-BRL), 100 U/mL penicillin, and 100 mg/mL streptomycin
(Gibco-BRL). Cells were plated and incubated for 4 or 20 hours in
6-well culture dishes (polystyrene culture dishes, Greiner). Cells were
cultured at 37°C in a humidified atmosphere with 5%
CO2. The absence of lipopolysaccharide
contamination in conditioned medium was confirmed by using E-TOXATE
(ICN), which has a sensitivity of 0.05 to 0.1 U according to the
manufacturer's protocol.
Preparation of Total RNA
Total RNA of MNCs was prepared by using Trizol (Gibco-BRL) and
following the manufacturer's protocol.
cDNA Synthesis
RNA aliquots of samples being compared with each other were
simultaneously reverse-transcribed into cDNA by using M-MLV
reverse transcriptase (Gibco-BRL) and oligo(dT)15
(Boehringer Mannheim).
Quantification of mRNA by Polymerase Chain Reaction (PCR)
Analysis
A PCR-based technique was used to quantify mRNA
steady-state levels in MNCs, as detailed
earlier.7 11 19 20 The position and references
for oligonucleotide primer (Mikrogen) selection are
shown in Table 1
. Typically,
nested amplification of cDNA templates was performed in a 50-µL total
reaction volume containing 10 µmol/L dNTP, 1.00 U DNA
Taq polymerase (Boehringer Mannheim), and
oligonucleotide primers (0.04 to 1.5 µmol/L). A
standard PCR cycle profile for quantitative analysis was as
follows: 94°C, 30 seconds; 54°C, 25 seconds; and 72°C, 30
seconds. Cycle numbers were chosen to ensure log-linear amplification.
Amplified products were separated on an ethidium bromide–stained
agarose gel (1.4%) and photographed under UV light (Polaroid 665
film), and the negatives were analyzed and quantified with an
UltraScan laser densitometer (Pharmacia). cDNA amplification
products were quantified relative to the respective ß-actin
signals.7 11 19 20
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Cloning and Nucleotide Sequencing
Amplified PCR fragments were ligated into pGEM-T vector
(Promega).20 Cloned PCR segments were sequenced
using the Sequenase 2.0 kit (Amersham) to confirm the presence of
correct amplification products.
ELISA
Cytokines and growth factors that accumulated in
conditioned medium of cultured monocytes were quantified using
commercial ELISAs for MCP-1 (R&D Systems) and IL-10 (Boehringer
Mannheim). PDGF-AA and PDGF-BB were determined using a sandwich
ELISA.27 The anti–PDGF A-chain monoclonal
antibody (127.2.2.2.2) was kindly provided by Zymogenetics and used for
capture of PDGF-AA, and a rabbit anti–PDGF-A polyclonal antibody
(Santa Cruz Biotechnology) was used for detection. For measurement of
PDGF-BB, a monoclonal antibody (PGF-007) was kindly provided by Mochida
Pharmaceutical Co (Tokyo, Japan) and used for capture, and a rabbit
polyclonal antibody (Santa Cruz Biotechnology) was used for
detection.
Plasma phospholipid fatty acid compositions were determined as described previously.7 28
Statistics
The data are expressed as mean±SD. Student's 2-tailed
t test was applied, and P
0.05 was regarded as
statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Volunteer Study
Dietary interventions for 4 weeks with all study capsules were well tolerated by all 28 volunteers, and no side effects were reported. The numbers of capsules returned indicated complete compliance by the volunteers, which was confirmed by analysis of plasma phospholipid fatty acid compositions (Table 2
). Cholesterol, LDL, HDL,
triglycerides, or any of the other safety or routine
parameters were in the normal range in all groups of
healthy volunteers initially and at the end of the study.
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Gene Expression in Unstimulated, Human MNCs
IL-10 mRNA steady-state levels in unstimulated MNCs were low: in
21 of 56 samples they were below the level of detection. PDGF-A,
PDGF-B, MCP-1, and HB-EGF mRNA levels were detectable in all 56
preparations of unstimulated, freshly isolated MNCs (Figure 1). mRNA steady-state levels of these
genes in MNCs of volunteers without dietary intervention revealed no
significant alterations (Figures 1 and 5 through 7). Similarly, neither
dietary -6 nor -9 fatty acids altered the mRNA steady-state
levels of PDGF-A, MCP-1, HB-EGF, and IL-10 in unstimulated MNCs
(Figures 2, 3, and 5 through 7. In unstimulated MNCs
of volunteers with -3 dietary supplementation, the mRNA steady-state
levels of IL-10 and HB-EGF were unchanged (Figure 4). However, PDGF-A, PDGF-B, and MCP-1
mRNA steady-state levels in unstimulated, freshly isolated MNCs were
reduced by 25±10%, 31±13%, and 40±14%, respectively
(P<0.05), after dietary -3 fatty acid ingestion (Figures 4 through 7). Taken together, these data show that in unstimulated,
human MNCs, only dietary intervention with -3 fatty acids reduced
MCP-1, PDGF-A, and PDGF-B mRNA steady-state levels.
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Gene Expression in Adherence-Stimulated Monocytes
Monocytes stimulated by adherence obtained from control
volunteers and from volunteers ingesting -6 or -9 fatty acids for
4 weeks showed no significant change in mRNA steady-state levels of
PDGF-A, PDGF-B, MCP-1, HB-EGF, and IL-10 (Figures 1 through 3
and
5 through 7). Dietary supplementation
with -3 fatty acids left HB-EGF and IL-10 mRNA steady-state levels
in monocytes stimulated by adherence unaltered (Figure 4). However,
MCP-1, PDGF-A, and PDGF-B mRNA steady-state levels were reduced in
monocytes stimulated by adherence for 4 hours, by 35±20%, 25±6%,
and 20±15%, respectively (Figures 4 through 7, all
P<0.05). In monocytes stimulated by adherence for 20 hours,
MCP-1, PDGF-A, and PDGF-B mRNA steady-state levels were reduced by
30±8%, 25±13%, and 20±15%, respectively, after -3 fatty acid
dietary intervention for 4 weeks (Figures 4 through 7, all
P<0.05). Taken together, these data indicate that in
monocytes stimulated by adherence ex vivo, mRNA steady-state levels of
PDGF-A, PDGF-B, and MCP-1 were reduced only by dietary -3 fatty
acids.
Accumulation of Cytokines and Growth Factors in
Conditioned Medium
PDGF-A, PDGF-B, MCP-1, and IL-10 were detectable in conditioned
media of all samples of monocytes stimulated by adherence for 20 hours.
Accumulated amounts were close to the respective assay's detection
limits and revealed no significant differences in any group on the
respective dietary interventions.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the current study, we demonstrate that supplementing the diet of volunteers with
-3, but not with -6 or -9, fatty acids
reduces PDGF-A, PDGF-B, and MCP-1 mRNA steady-state levels in
unstimulated MNCs and that this reduction persists after stimulating
human monocytes by adherence ex vivo. Thus, we have extended our
earlier observations on decreased PDGF-A and PDGF-B mRNA steady-state
levels in unstimulated human MNCs after dietary -3 fatty acid
supplementation.7
As yet, interactions of dietary fatty acids and gene expression
have hardly been investigated in humans.29 30 31
This is probably due to methodological problems. Our cell preparation
procedure results in platelet-free
MNCs.7 11 19 20 28 For monocyte activation and
differentiation, we decided to use an established model ex vivo, ie,
their adherence to polystyrene.14 15 32 33
Activating monocytes ex vivo by adherence requires the presence of
serum factors.34 Therefore, we left the monocytes
to adhere for 4 or 20 hours in the presence of 5% serum from the
respective donor at the respective time point. Nested PCR is capable of
detecting and quantifying minute amounts of
mRNA.7 11 19 20 On adherence, few monocyte mRNA
levels respond in a predictable and reproducible
manner.11 However, PDGF-A, PDGF-B, and MCP-1 mRNA
steady-state levels in unstimulated MNCs were reproducible and
constant11(not shown) and responded to adherence
predictably and reproducibly under constant dietary
conditions11 (data not shown; Figures 1, 5, 6, and 7).
Thus, by using an established model and our
methods,7 11 19 20 28 we have demonstrated that
the genes for PDGF-A, PDGF-B, and MCP-1 are expressed reproducibly and
are quantitatively constant in unstimulated human MNCs and that human
MNC stimulation by adherence ex vivo elicits reproducible and
predictable responses in mRNA levels.
Previously, we demonstrated reduced PDGF-A and PDGF-B, but not
insulin-like growth factor, platelet-derived
endothelial cell growth factor, and transforming growth
factorß, mRNA levels in unstimulated MNCs after dietary
supplementation with -3 fatty acids for 1 and 6
weeks.7 19 We now confirm our findings with
respect to PDGF-A and PDGF-B, though to a quantitatively somewhat
lesser degree, probably owing to interindividual differences. We extend
our observations to MCP-1, another growth factor implicated in the
pathogenesis of
atherosclerosis15,18,35,36: mRNA
levels of MCP-1 were also markedly reduced after supplementation of the
volunteers' diets with -3 fatty acids. (Figures 4 and 7). To our
knowledge, no modality has previously been demonstrated to affect MCP-1
mRNA steady-state levels. Moreover, we have now demonstrated the
reduction in mRNA levels to be induced solely by -3, and not by
-6 or -9, fatty acids. This result suggests that dietary -3
fatty acids, but no other class of unsaturated fatty acids,
specifically regulate gene expression of PDGF-A, PDGF-B, and MCP-1.
From our data, we cannot delineate the underlying mechanisms. We can,
however, exclude a nonspecific effect on gene expression exerted by
dietary unsaturated fatty acids. The effect we observed appears to be a
consequence of distinct regulatory pathways responsive to -3 fatty
acids. In vitro, in human monocytic cells, -3, but not -6, fatty
acids significantly reduced the mRNA and protein expression of CD36,
also known as the scavenger receptor for oxidized
LDL.37 As in the current investigation, a
mechanism of action of -3 fatty acids was not delineated.
Future investigations will be needed to elucidate regulatory
pathways responsible for our findings.
Reduced PDGF-A, PDGF-B, and MCP-1 mRNA steady-state levels in
unstimulated MNCs translate into lower respective mRNA steady-state
levels in monocytes stimulated by adherence in cells from donors
supplementing their diets with -3 fatty acids only (Figures 4 through 7). IL-10 and HB-EGF mRNA steady-state levels were not affected
by ingestion of -3 fatty acids after cell adherence. In control
volunteers, as in the volunteers ingesting -6 or -9 fatty acids,
all mRNA steady-state levels investigated were unaffected in monocytes
stimulated by adherence (Figures 1 through 3 and 5 through 7). Reduced
gene expression in unstimulated MNCs translated into quantitatively
comparable reduced gene expression in monocytes stimulated by adherence
(Figures 4 through 7). Thus, -3 fatty acids seem to affect less the
increase in response to adherence than conserve reduced PDGF-A, PDGF-B,
and MCP-1 mRNA steady-state levels of the unstimulated MNCs.
In vitro, putative mechanisms of action have been described
relating dietary components and gene expression; transcription factors
related to the carbohydrate-response region may be involved in
mediating unsaturated fatty acid signaling.38
Nuclear factor peroxisome proliferator–activated receptor
might be involved.31 39 In experimental animals,
dietary -3 fatty acids regulated apoA-I, apoA-II, and acyl-coenzyme
A oxidase gene expression.40 Antioxidant vitamins
may play a role in regulation of gene expression of immune
cells.41 However, because it is unclear whether
the mechanisms described in vitro can be applied to the human in
vivo/ex vivo situation, future investigations will focus on the
mechanisms of action responsible for the effects of dietary -3 fatty
acids on human monocyte gene expression.
The effect of supplementing a human diet with -6 or -9
fatty acids with respect to MNC or monocyte gene expression ex vivo has
not yet been studied to our knowledge. In vitro, eg, in
hepatocytes, a number of different unsaturated fatty acids
reduced mRNA levels for pyruvate kinase, fatty acid synthase, and the
S14 protein indiscriminately.42
Epidemiologically, a high intake of -6 polyunsaturated fatty acids
is correlated with a high rather than a low incidence of
cardiovascular disease,43 whereas
a high intake of -9 fatty acids, as in the Mediterranean diet, is
correlated with a low incidence of cardiovascular
disease.44 Clearly, the effects of dietary -6
or -9 fatty acids on human gene expression as close as possible to
the in vivo situation merit further study.
The current investigation was primarily aimed at alterations in
human MNC and monocyte gene expression after ingestion of different
classes of unsaturated fatty acids. Only limited amounts of blood can
be obtained from a volunteer, resulting in small sample sizes.
Therefore, we were unable to demonstrate whether alterations in gene
expression were translated into alterations in the respective
product levels. In other studies, after dietary intervention with
-3 fatty acids, alterations on the human monocyte/macrophage
product level have been observed, like reductions in IL-1ß, IL-6,
and tumor necrosis factor formation after stimulation with strong
agents like lipolysaccharide.45 46 47 Thus,
a stronger stimulus on a larger sample will be used in our future
investigations to clarify the effect of dietary -3 fatty acids on
PDGF and MCP-1 on the product level.
In conclusion, we demonstrate that PDGF-A, PDGF-B, and MCP-1 mRNA
steady-state levels in unstimulated MNCs and in
adherence-activated MNCs were decreased after supplementing the
volunteers' diets with -3 fatty acids. This decrease was
specifically induced by dietary -3 fatty acids, since neither
dietary -6 nor -9 fatty acids altered the mRNA steady-state
levels investigated. Thus, ingestion of -3 fatty acids by volunteers
specifically reduces gene expression of PDGF-A, PDGF-B, and MCP-1,
factors that are currently thought to play an important role in
the pathogenesis of human atherosclerosis.
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Acknowledgments |
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This study was supported by Deutsche Forschungsgemeinschaft (Scha 398 to F.H., R.K., C.v.S.) and Wilhelm Sander-Stiftung (to K.H.B.). We thank the Biomedical Test Materials Program of the US Department of Commerce, National Oceanic and Atmospheric Administration/National Marine Fisheries Services, Charleston, SC, for providing the fatty acid concentrates.
Received March 2, 1998; accepted June 2, 1998.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Burr ML, Fehily A, Gilbert JF, Holliday RM, Sweetnam PM, Elwood PC, Deadman NM. Effects of changes in fat, fish, and fibre intakes on death and myocardial infarction: diet and reinfarction trial (DART). Lancet. 1989;2:757–761.[Medline] [Order article via Infotrieve]
2. Leaf A, Kang JX. Prevention of cardiac sudden death by n-3 fatty acids: a review of the evidence. J Intern Med. 1996;240:5–12.[Medline] [Order article via Infotrieve]
3. von Schacky C, Angerer P, Kothny W, Theisen K, Mudra H. Study on prevention of coronary atherosclerosis with marine omega-3 fatty acids (SCIMO): first results of a randomized double blind study. Can J Cardiol. 1997;13(suppl B):42B. Abstract.
4.
von Schacky C. Prophylaxis of
atherosclerosis with marine -3 fatty
acids: a comprehensive strategy. Ann Intern Med. 1987;107:890–899.
5. Endres S, von Schacky C. n-3 Polyunsaturated fatty acids and human cytokine synthesis. Curr Opin Lipidol. 1996;7:48–52.[Medline] [Order article via Infotrieve]
6. Harris WS. n-3 Fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997;65(suppl 5):1645S–1654S.
7.
Kaminski W, Jendraschak E, Kiefl R, von Schacky C.
Dietary -3 fatty acids lower levels of platelet-derived
growth factor mRNA in human mononuclear cells. Blood. 1993;81:1871–1879.
8. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]
9. Ross R. Cell biology of atherosclerosis. Annu Rev Physiol. 1995;57:791–804.[Medline] [Order article via Infotrieve]
10. Rappolee DA, Werb Z. Macrophage-derived growth factors. Curr Top Microbiol Immunol. 1992;181:87–140.[Medline] [Order article via Infotrieve]
11. Jendraschak E, Kaminski W, Kiefl R, von Schacky C. IGF-1, PDGF, and CD 18 are adherence-responsive genes: regulation during monocyte differentiation. Biochim Biophys Acta. 1998;1396:320–335.[Medline] [Order article via Infotrieve]
12.
Cushing SD, Fogelman AM. Monocytes may amplify their
recruitment into inflammatory lesions by inducing monocyte chemotactic
protein. Arterioscler Thromb. 1992;12:78–82.
13. Adams DH, Russell ME, Hancock WW, Sayegh MH, Wyner LR, Karnovsky MJ. Chronic rejection in experimental cardiac transplantation: studies in the Lewis-F344 model. Immunol Rev. 1993;134:5–19.[Medline] [Order article via Infotrieve]
14.
Shaw RJ, Doherty DE, Ritter AG, Benedict SH, Clark RA.
Adherence-dependent increase in human monocyte PDGF(B) mRNA is
associated with increases in c-fos, c-jun, and EGR2 mRNA. J
Cell Biol. 1990;111:2139–2148.
15. Gruss HJ, Brach MA, Schumann RR, Herrmann F. Regulation of MCP-1/JE gene expression during monocytic differentiation. J Immunol. 1994;153:4907–4914.[Abstract]
16. Li L, Elliott JF, Mosmann TR. IL-10 inhibits cytokine production, vascular leakage, and swelling during T helper 1 cell-induced delayed-type hypersensitivity. J Immunol. 1994;153:3967–3978.[Abstract]
17.
Dluz SM, Higashiyama S, Damm D, Abraham JA, Klagsbrun
M. Heparin-binding epidermal growth factor-like growth factor
expression in cultured fetal human vascular smooth muscle cells:
induction of mRNA levels and secretion of active mitogen. J
Biol Chem. 1993;268:18330–18334.
18. Rollins BJ. Monocyte chemoattractant protein 1: a potential regulator of monocyte recruitment in inflammatory disease. Mol Med Today. 1996;2:198–204.[Medline] [Order article via Infotrieve]
19. Jendraschak E, Kaminski W, Hessel F, Kiefl R, von Schacky C. Growth factor mRNA profiles in unstimulated human mononuclear cells: identification of genes which are constitutively and variably expressed. Biochem Biophys Res Commun. 1993;196:25–31.[Medline] [Order article via Infotrieve]
20.
Kaminski W, Jendraschak E, Baumann K, Kiefl R, Fischer
S, Marcus A, Broekman M, von Schacky C. Human mononuclear cells express
12-LX: coordinated mRNA regulation with 5-LX and FLAP genes.
Blood. 1996;87:331–340.
21.
Vieira P, de Waal-Malefyt R, Dang MN, Johnson KE,
Kastelein R, Florentine DF, deVries JE, Roncarolo MG, Mosmann TR, Moore
KW. Isolation and expression of human cytokine synthesis
inhibitory factor cDNA clones: homology to Epstein-Barr
virus open reading frame BCRF1. Proc Natl Acad Sci U S A. 1991;88:1172–1176.
22.
Higashiyama S. Abraham JA, Miller J, Fiddes JC,
Klagsbrun M. A heparin-binding growth factor secreted by
macrophage-like cells that is related to EGF.
Science. 1991;251:936–939.
23. Furutani Y, Nomura H, Notake M, Oyamada Y, Fukui T, Yamada M, Larsen GG, Oppenheim JJ, Matsushima K. Cloning and sequencing of the cDNA for human monocyte chemotactic and activating factor (MCAF). Biochem Biophys Res Commun. 1989;159:249–255.
24.
Rao CD, Igarashi H, Chiu I-M, Robbins KC, Aaronson SA.
Structure and sequence of the human c-sis/platelet derived growth
factor 2 (SIS/PDGF2) transcriptional unit. Proc Natl Acad Sci
U S A. 1986;83:2392–2396.
25.
Ponte P, Ng SY, Engel J, Gunning P, Kedes L.
Evolutionary conservation in the untranslated regions of actin mRNAs:
DNA sequence of a human ß-actin cDNA. Nucleic Acids
Res. 1984;12:1687–1696.
26. Betsholtz C, Johnsson A, Heldin CH, Westermark B, Lind P, Urdea MS, Eddy R. Shows TB, Philpott K, Mellor AL, Knott TJ, Scott J. cDNA sequence and chromosomal localization of human platelet-derived growth factor A-chain and its expression in tumour cell lines. Nature. 1986. 320:695–699.
27. Kraiss LW, Raines EW, Wilcox JN, Seifert RA, Barrett TB, Kirkman TR, Hart CE, Bowen PD, Ross R, Clowes AW. Regional expression of the platelet-derived growth factor and its receptors in a primate graft model of vessel wall assembly. J Clin Invest. 1993;92:338–348.
28. von Schacky C, Fahrer C, Fischer S. Catabolism of leukotriene B5 in humans. J Lipid Res. 1990;31:1831–1838.[Abstract]
29. Simopoulos AP. The role of fatty acids in gene expression: health implications. Ann Nutr Metab. 1996;40:303–311.[Medline] [Order article via Infotrieve]
30. FitzGerald GA, Barry P. Dietary factors in thrombosis and hemostasis: summary and conclusions. Am J Clin Nutr. 1997;65(suppl 5):1699S–1701S.
31. Clarke SD, Jump DB. Polyunsaturated fatty acid regulation of hepatic gene transcription. Lipids. 1996;126:S7–S11.
32. Heinel LA, Singleton D, Miller M, Frewin MB, Gudewicz PW. Monocyte adherence to the subendothelial basement membrane increases interleukin-8 gene expression and antigen release. Inflammation. 1995;19:517–527.[Medline] [Order article via Infotrieve]
33. Martin DK, Bootcov MR, Campbell TJ, French PW, Breit SN. Human macrophages contain a stretch-sensitive potassium channel that is activated by adherence and cytokines. J Membr Biol. 1995;147:305–315.[Medline] [Order article via Infotrieve]
34.
McNally AK, Anderson JM. Complement C3 participation in
monocyte adhesion to different surfaces. Proc Natl Acad Sci
U S A. 1994;91:10119–10123.
35. Seino Y, Ikeda U, Takahashi M, Hojo Y, Irokawa M, Kasahara T, Shimada K. Expression of monocyte chemoattractant protein-1 in vascular tissue. Cytokines. 1995;7:575–579.
36. Ikeda U, Okada K, Ishikawa SE, Saito T, Kasahara T, Shimada K. Monocyte chemoattractant protein 1 inhibits growth of rat vascular smooth muscle cells. Am J Physiol. 1995;37:H1021–H1026.
37. Pietsch A, Weber C, Goretzki M, Weber PC, Lorenz RL. N-3 but not N-6 fatty acids reduce the expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells. Cell Biochem Funct. 1995;13:211–216.[Medline] [Order article via Infotrieve]
38. Baillie RA, Jump DB, Clarke SD. Specific effects of polyunsaturated fatty acids on gene expression. Curr Opin Lipidol. 1996;7:53–55.[Medline] [Order article via Infotrieve]
39.
Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The
peroxisome proliferator-activated receptor-
is a
negative regulator of macrophage activation. Nature. 1998;391:79–82.[Medline]
[Order article via Infotrieve]
40. Berthou L, Saladin R, Yaqoob P, Branellec D, Calder P, Fruchart JC, Denefle P, Auwerx J, Staels B. Regulation of rat liver apolipoprotein A-I, apolipoprotein A-II and acyl-coenzyme A oxidase gene expression by fibrates and dietary fatty acids. Eur J Biochem. 1995;232:179–187.[Medline] [Order article via Infotrieve]
41.
Meydani SN. Interaction of -3 polyunsaturated
fatty acids and vitamin E on the immune response. In: Galli C,
Simopoulos AP, Tremoli E, eds. Fatty Acids and Lipids: Biological
Aspects. Basel, Switzerland: Karger; 1994:155–161.
42. Jump DB, Clarke SD, Thelen A, Liimatta M. Coordinate regulation of glycolytic and lipogenic gene expression by polyunsaturated fatty acids. J Lipid Res. 1994;35:1076–1084.[Abstract]
43.
Yam D, Eliraz A, Berry EM. Diet and disease: the
Israeli paradox: possible dangers of a high -6 polyunsaturated
fatty acid diet. Isr J Med Sci. 1996;32:1134–1143.[Medline]
[Order article via Infotrieve]
44. Renaud S, Delorgeril M, Delaye J, Guidollet J, Jacquard F, Mamelle N, Martin JL, Monjaud I, Salen P, Toubol P. Cretan Mediterranean diet for prevention of coronary heart disease. Am J Clin Nutr. 1995;61:S1360–S1367.
45.
Caughey GE, Mantzioris E, Gibson RA, Cleland LG, James
MJ. The effect on human tumor necrosis factor-
and interleukin
1-ß production of diets enriched in n-3 fatty acids from
vegetable oil or fish oil. Am J Clin Nutr. 1996;63:116–122.
46. Abbate R, Gori AM, Martini F, Brunelli T, Filippini M, Francalanci I, Paniccia R, Prisco D, Gensini GF, Neri SG. n-3 PUFA supplementation, monocyte PCA expression and interleukin-6 production. Prostaglandins Leukot Essent Fatty Acids. 1996;54:439–444.[Medline] [Order article via Infotrieve]
47.
Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonneman
G, van der Meer JWM, Cannon JG, Togers TS, Klempner MS, Weber PC,
Schaefer EJ, Wolff SM, Dinarello CA. The effect of dietary
supplementation with -3 polyunsaturated fatty acids on the
synthesis of interleukin-1 and tumor necrosis factor by mononuclear
cells. N Engl J Med. 1989;320:265–271.[Abstract]
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