(Received for publication, November 14, 1995)
From the
Regulation of expression of the scavenger receptor is thought to
play a critical role in the accumulation of lipid by macrophages in
atherosclerosis. Tumor necrosis factor- (TNF-
) has been shown
to suppress macrophage scavenger receptor function (van Lenten, B. J.,
and Fogelman, A. M.(1992) J. Immunol. 148, 112-116).
However, the mechanism by which it does so is unknown. We evaluated the
mechanism by which TNF-
inhibited macrophage scavenger receptor
surface expression and binding of acetylated low density lipoprotein
(aLDL). Binding of aLDL to phorbol 12-myristate 13-acetate
(PMA)-differentiated THP-1 macrophages was suppressed by TNF-
in a
dose-dependent manner. Inhibition of aLDL binding was paralleled by a
reduction of macrophage scavenger receptor protein as detected by the
Western blot. TNF-
partially decreased macrophage scavenger
receptor mRNA steady state levels in PMA-differentiated THP-1
macrophages, a result that was confirmed by reverse
transcription-polymerase chain reaction. PMA increased the luciferase
activity driven by the macrophage scavenger receptor promoter in the
transfected cells, whereas TNF-
partially reduced luciferase
activity. However, macrophage scavenger receptor mRNA half-life was
dramatically reduced in cells treated with TNF-
relative to
untreated cells. Reduction in macrophage scavenger receptor message in
response to TNF-
was dependent on new protein synthesis because it
was blocked by cycloheximide. These results indicate that TNF-
regulates macrophage scavenger receptor expression in
PMA-differentiated THP-1 macrophages by transcriptional and
post-transcriptional mechanisms but principally by destabilization of
macrophage scavenger receptor mRNA.
Macrophage scavenger receptors bind oxidized low density
lipoprotein (LDL) ()and acetylated LDL (aLDL), as well as
other polyanionic ligands, and were initially identified by their
ability to bind charge modified LDL but not native LDL(2) .
Unlike the LDL receptor, expression of the macrophage scavenger
receptor is not down-regulated by high levels of intracellular
cholesterol. Because of the potential role of this receptor in
mediating cholesteryl ester accumulation by macrophages during
atherosclerosis, the regulation of expression of these receptors is of
considerable important and interest. Circulating monocytes express
little or no macrophage scavenger receptor, but receptor mRNA and
surface expression are dramatically increased because monocytes
differentiate into macrophages in tissue culture. Treatment of
monocytes or THP-1 cells (a human monocytic cell line) with phorbol-12
myristate 13-acetate (PMA) also promotes differentiation and induces
macrophage scavenger receptor expression(3) . Similarly,
macrophage colony-stimulating factor (M-CSF) augments macrophage
scavenger receptor expression(4) .
Inhibition of macrophage
scavenger receptor expression and activity has been reported in
response to interferon- (IFN-
)(5, 6) ,
transforming growth factor-
1 (TGF-
1)(7) , all-trans
retinoic acid, dexamethasone(8) , platelet secretary
products(9, 10, 11) , and lymphocyte culture
supernatants(12) . Bacterial lipopolysaccharide (LPS), a potent
activator of mononuclear phagocytes, can inhibit scavenger receptor
activity in human macrophages(13) . Most of the inhibitory
activity of LPS on the macrophage scavenger receptor could be blocked
with an antibody to TNF-
(1) , suggesting that TNF-
,
which is synthesized in response to LPS, mediated the LPS effect.
However, the molecular mechanism(s) by which TNF-
inhibits
macrophage scavenger receptor activity have not been elucidated. In
this study, we demonstrate that TNF-
inhibits macrophage scavenger
receptor binding activity, surface protein expression, and mRNA levels,
with subsequent down-regulation of macrophage scavenger
receptor-mediated ACAT activity and cholesterol esterification in
PMA-differentiated THP-1 macrophages. Although macrophage scavenger
receptor transcriptional activity was modestly reduced in response to
TNF-
, in the presence of actinomycin D, macrophage scavenger
receptor mRNA half-life was significantly reduced, implying that
TNF-
inhibits macrophage scavenger receptor expression principally
by post-transcriptional decreases in macrophage scavenger receptor mRNA
stability.
PMA and M-CSF equivalently increased the specific binding (4
°C) of I-aLDL to THP-1 macrophages compared with
untreated THP-1 monocytes (Fig. 1A). Co-treatment of
PMA- or M-CSF-differentiated THP-1 cells with TNF-
reduced
specific binding of
I-aLDL to baseline (control) levels (Fig. 1A) in a dose-dependent manner (Fig. 2).
The effect of TNF-
on
I-aLDL binding resulted from a
decrease in the number of binding sites (B
)
without significant change in receptor affinity (K
). Scatchard analysis (Fig. 1B)
demonstrated that PMA or M-CSF increased B
by 6-
or 7-fold, respectively, as compared with undifferentiated THP-1
monocytes (undifferentiated THP-1 monocytes (control) = 1.66
10
sites/cell; PMA-differentiated THP-1
macrophages) = 9.71
10
sites/cell; M-CSF
treated THP-1 cells = 10.6
10
sites/cell).
The B
of undifferentiated THP-1 monocytes
(control), PMA-differentiated THP-1 macrophages treated with TNF-
(PMA + TNF-
), as well as THP-1 monocytes treated with
TNF-
and M-CSF-differentiated THP-1 macrophages treated with
TNF-
, (data not shown) were equivalent (each approximately
1.23-1.66
10
sites/cell). K
values were not significantly altered by any treatment (Fig. 1B).
Figure 1:
Effect of TNF- on aLDL-specific
binding. A, human THP-1 monocytes were grown to about 1
10
cells/ml in 12-well plates and then placed in
serum-free medium (Control, undifferentiated THP-1 monocytes),
serum-free medium with 150 nM PMA (PMA, THP-1
macrophages), serum-free medium with PMA + 200 units/ml TNF-
, (PMA + TNF-
), or serum-free medium with 3.5 nM M-CSF (M-CSF), as well as serum-free medium with M-CSF
+ TNF-
, or serum-free medium with TNF-
alone (data not
shown), for 24 h prior to the addition of the indicated concentration
of
I-aLDL. Binding studies were performed for 2 h at 4
°C as described under ``Experimental Procedures.'' The points represent the mean of triplicate wells ± S.E.
and are representative of two separate experiments. B,
Scatchard analysis of A.
Figure 2:
Dose response effect of TNF- on aLDL
binding in PMA-differentiated THP-1 macrophages. PMA-differentiated
THP-1 macrophages were incubated with varying concentrations of
TNF-
(1-300 units/ml). Specific aLDL binding (
I-aLDL, 20 µg/ml) was performed as described under
``Experimental Procedures.''
Western analysis (Fig. 3) revealed
that little or no macrophage scavenger receptor protein was expressed
in THP-1 monocytes. PMA-differentiated THP-1 macrophages expressed
scavenger receptor protein, but TNF- suppressed the expression of
macrophage scavenger receptor protein when THP-1 cells co-incubated
with PMA. TNF-
did not cause any signs of general cellular
toxicity. Cells treated with PMA/TNF-
remained adherent and
morphologically similar to PMA-treated cells (THP-1 macrophages).
Furthermore, there was no decrease in protein content or cell number or
any increase in the uptake of trypan blue (data not shown).
Figure 3:
Western blot analysis of MSR protein
expression in PMA-differentiated THP-1 macrophages. THP-1 cells were
treated as indicated. Lane 1, THP-1 monocytes treated with PMA
(150 nM) for 24 h and differentiated into THP-1 macrophages; lane 2, THP-1 monocytes treated with PMA (150 nM)
+ TNF- (200 units/ml) for 24 h; lane 3, control,
undifferentiated THP-1 monocytes. The detailed method is described
under ``Experimental Procedures.'' The molecular mass (M.W.; in kDa) standards are indicated on the right
side. The arrows on the left side represent
monomeric and dimeric forms of MSR. This experiment is representative
of three similar experiments.
To
dissect the molecular mechanisms by which TNF- suppressed
macrophage scavenger receptor protein expression, we initially examined
the influence of TNF-
on macrophage scavenger receptor mRNA
levels. Northern blot analyses of PMA-differentiated THP-1 macrophages
revealed a time-dependent increase in macrophage scavenger receptor
mRNA steady state levels in response to PMA (Fig. 4, A and B). Expression peaked at 48 h. Macrophage scavenger
receptor mRNA was not detected in undifferentiated THP-1 monocytes (not
treated with PMA), and TNF-
had no effect on this baseline
expression. TNF-
decreased macrophage scavenger receptor mRNA
expression by 80 (at 20 h) and 70% (at 48 h), respectively, in
PMA-differentiated cells relative to PMA-differentiated cells not
treated with TNF-
(THP-1 macrophages) (Fig. 4, A and B). RT-PCR demonstrated that TNF-
decreased both
human macrophage scavenger receptor types SR-AI and SR-AII mRNA in
PMA-treated THP-1 macrophages (Fig. 4C). Dose response
experiments showed that maximal inhibition of macrophage scavenger
receptor mRNA levels (similar to macrophage scavenger receptor surface
expression as determined by aLDL binding) by TNF-
occurred at 200
units/ml (data not shown).
Figure 4:
TNF- decreases MSR mRNA synthesis in
PMA-differentiated THP-1 macrophages at steady state level. A,
total RNA was isolated from THP-1 cells grown in serum-free medium (Control, THP-1 monocytes, samples 1 and 5),
medium containing PMA (150 nM) (PMA, THP-1
macrophages, samples 2 and 6), medium containing PMA
(150 nM) + TNF-
(200 units/ml) (PMA + TNF-
, samples 3 and 7), or medium
containing TNF-
(200 units/ml) (TNF-
, samples 4 and 8) for 20 and 48 h, respectively. Northern blots were
hybridized with
P-labeled cDNAs of MSR or 28 S. The
respective autoradiograms with MSR and 28 S bands are labeled and
indicated with arrows. B, histograms represent quantification
by PhosphorImager® of MSR mRNA normalized by comparison with 28 S
ribosomal RNA. All data are expressed as a percentage of sample 2, i.e. PMA-differentiated THP-1 macrophages. Similar results
were obtained in three separate experiments. C, RT-PCR
analysis of the expression of macrophage scavenger receptor types SR-AI
and SR-AII mRNA in THP-1 monocytes, PMA-differentiated THP-1
macrophages in the absence and the presence of TNF-
. Ethidium
bromide-stained agarose gel with MSR type SR-AI at 447 base pairs and
MSR type SR-AII at about 285 base pairs. Lane 1, 100 base pair
DNA ladder; lane 2, THP-1 monocytes; lane 3,
PMA-differentiated THP-1 macrophages (24 h); lane 4, THP-1
cells with PMA + TNF-
(24 h); lane 5, DNA molecular
weight marker V from Boehringer Mannheim. The detailed method is
described under ``Experimental Procedures.'' There was no
detectable MSR type SR-AI and SR-AII mRNA in THP-1 cells with TNF-
(data not shown). The arrows indicate MSR types SR-AI and
SR-AII. The results shown are representative of three independent
experiments.
To examine if decreased macrophage
scavenger receptor mRNA expression in response to TNF- in
PMA-differentiated THP-1 macrophages resulted from decreased
transcription of the macrophage scavenger receptor gene, assays for
luciferase activity driven by macrophage scavenger receptor gene
promoter were performed. THP-1 cells were transiently transfected by
the DEAE-dextran sulfate method with plasmid MSR-Luc luciferase
construct consisting of 5` upstream sequences of the macrophage
scavenger receptor promoter region. Luciferase activity was measured in
untreated cells, cells treated with PMA, and cells treated with PMA
+ TNF-
(200 units/ml). PMA induced luciferase activity driven
by the macrophage scavenger receptor gene promoter by 3.5-fold.
TNF-
reduced luciferase activity by 20% after 12 h (Fig. 5).
Figure 5:
TNF- down-regulates MSR gene
transcriptional activity in PMA-differentiated THP-1 macrophages. THP-1
cells were transfected by the DEAE-dextran sulfate method with plasmid
MSR-Luc luciferase construct consisting of 5` upstream sequences of the
promoter region from MSR gene of THP-1 macrophages (e.g. plasmids HACLDL Xba-A1-luc promoter or HACLDL Xba-A1-luc Enhancer)
or control plasmid and co-transfected with
-galactosidase. After
24 h post-transfection, cells were treated with PMA (150 nM)
or PMA (150 nM) + TNF-
(200 units/ml). The
luciferase activities of transfected cells were measured at the
indicated time. The data are expressed as the means of quadruplicate
samples ± S.E. (p
0.05) and are representative of
three separate experiments..
To determine if TNF- reduced the level of
macrophage scavenger receptor mRNA by increasing its rate of
degradation, we measured the half-life of macrophage scavenger receptor
mRNA in the presence of the transcription inhibitor actinomycin D (5
µg/ml). TNF-
shortened the half-life of macrophage scavenger
receptor mRNA from 40 ± 3 to 10 ± 2 h (Fig. 6, A, B, and C). Therefore, the reduction in
macrophage scavenger receptor message by TNF-
appears to be
mediated principally by a post-transcriptional mechanism, namely,
accelerating the degradation of macrophage scavenger receptor mRNA.
Moreover, incubation of cells with the protein synthesis inhibitor
cycloheximide (10 µg/ml) prevented the decrease of macrophage
scavenger receptor mRNA at both 3 and 6 h in TNF-
-treated samples (Fig. 7). These findings suggest that the effect(s) of TNF-
on macrophage scavenger receptor mRNA destabilization requires new
protein synthesis.
Figure 6:
Northern blots showing the effects of
TNF- on the half-life of MSR mRNA in the presence actinomycin D.
Human THP-1 monocytes were treated with PMA (150 nM) +
TNF-
(200 units/ml) (A) or PMA (150 nM) alone (B) for 24 h before addition of actinomycin D (5 µg/ml).
Total RNA was harvested at the indicated times and analyzed by Northern
blotting with
P-labeled probes of MSR and 28 S. C, mRNA in A and B were quantitated using a
PhosphorImager® and normalized by comparison of 28 S RNA. Northern
blot analyses shows MSR mRNA levels (relative intensity compared with
control sample at t = 0 h) as a semi-log function of
time in the presence of actinomycin D alone or in the combination with
TNF-
. The experiments were performed two
times.
Figure 7:
Northern blots showing reversal by
cycloheximide of the destabilizing effects of TNF- on MSR mRNA.
PMA-differentiated THP-1 macrophages were treated with cycloheximide
(10 µg/ml) for 1 h before the addition of TNF-
(200 units/ml).
PMA-differentiated THP-1 macrophages (PMA (Control)),
PMA-differentiated THP-1 macrophages treated with TNF-
(PMA
+ TNF-
), and PMA-differentiated THP-1 macrophages
treated with TNF-
and incubated with cycloheximide (PMA + TNF-
+ CHX) were harvested 3 and 6 h after exposure to
TNF-
. Northern blots were hybridized with
P-labeled
cDNAs of MSR and 28 S ribosomal RNA, quantitated by
PhosphorImager®, and normalized by comparison with 28 S. All of the
data are expressed as a percentage relative to THP-1 macrophages (t = 3 h). The relative intensity of MSR mRNA is plotted
against time. Pretreating THP-1 macrophages for 1 h with cycloheximide
had no effect on the basal level of MSR mRNA (data not shown). Similar
results were obtained in three separate
experiments.
Lastly, we characterized the role of TNF- in
macrophage scavenger receptor-mediated CE metabolism by evaluating
parameters of the CE cycle. ACAT activity (Fig. 8A) as
well as esterification of free cholesterol with
[
H]oleic acid to CE (Fig. 8B)
were evaluated in PMA-differentiated THP-1 macrophages and
PMA-differentiated THP-1 cells treated with TNF-
. TNF-
caused
a significant (65%) reduction in ACAT activity and a similar decrease
in the synthesis of nascent CE from free fatty acids as compared with
untreated cells. These decreases paralleled the decrease in aLDL
binding and most likely reflect a decrease in cholesterol delivery.
Finally, the effects of TNF-
on CE hydrolase activities were
measured, but no significant difference in acid CE hydrolase or neutral
CE hydrolase activities in response to TNF-
was observed (data not
shown).
Figure 8:
A, effect of TNF- on ACAT activity in
PMA-differentiated THP-1 macrophages. PMA-differentiated THP-1
macrophages were co-incubated with TNF-
(200 units/ml for 12 and
24 h) and homogenized after washing with ice-cold phosphate-buffered
saline. Homogenates were assayed for ACAT activity as described under
``Experimental Procedures.'' All of the data derived from the
group of THP-1 macrophages treated with TNF-
(asterisks)
are significantly (p < 0.05) different from the group of
THP-1 macrophages. The data represent the means of quadruplicate wells
± S.E. This figure is representative of three such
experiments. B, esterification of cholesterol is decreased in
TNF-
-treated PMA-differentiated THP-1 macrophages. Esterification
of cholesterol was performed as described under ``Experimental
Procedures.'' Cell lipids were extracted, and radioactivity in
cellular CE was measured after separation by thin layer chromatography.
All data derived from the group of THP-1 macrophages treated with
TNF-
(asterisks) are significantly (p < 0.05)
different from the group of THP-1 macrophages. The data represent the
means of quadruplicate wells ± S.E. This figure is
representative of three such experiments.
Expression of the macrophage scavenger receptor (acetylated LDL receptor) occurs as monocytes differentiate into macrophages in tissue culture over a period of several days, a process that mimics what is thought to occur as blood monocytes enter tissue to become tissue macrophages. These differentiation events can be mimicked by treating monocytes or some (but not all) monocytic cell lines, such as THP-1 cells, with PMA. PMA activates protein kinase C (8, 38) in THP-1 cells concomitantly with the differentiation of this cell type into macrophage-like cells(7, 17, 18) .
Fogelman and his
colleagues had previously shown that LPS inhibited scavenger receptor
activity in human macrophages (13) and that this inhibitory
effect could be blocked with an antibody to TNF-(1) . We
utilized PMA-differentiated THP-1 macrophages to evaluate the molecular
mechanisms by which TNF-
inhibited macrophage scavenger receptor
expression. The inhibitory effect of TNF-
on macrophage scavenger
receptor expression and activity is comparable with previously
demonstrated inhibitory effects of IFN-
and TGF-
1 on the
macrophage scavenger receptor. TNF-
inhibited macrophage scavenger
receptor activity (aLDL binding, Fig. 1), protein synthesis (Fig. 3), and mRNA steady state levels (Fig. 4).
TNF-
caused a 6-fold decrease in macrophage scavenger receptor
number without affecting receptor affinity in PMA-differentiated THP-1
macrophages. IFN-
inhibited macrophage scavenger receptor activity
in human (5) or mouse monocyte-derived macrophages(6) .
IFN-
inhibited binding, internalization, and degradation of aLDL
and reduced macrophage scavenger receptor mRNA steady state levels in
comparison with untreated cells. This resulted in a reduction of
cholesterol and CE content. Inhibition of binding resulted from
decreased numbers of aLDL binding sites without a significant change in
receptor affinity. Similarly, TGF-
1 inhibited macrophage scavenger
receptor activity and mRNA in PMA-differentiated THP-1 macrophages (7) and caused a decrease in binding of aLDL, degradation of
aLDL, and ACAT activity relative to PMA-differentiated THP-1 cells.
TGF-
1 caused a 2-fold decrease in macrophage scavenger receptor
number as well as a decrease in receptor affinity.
Inhibition of
macrophage scavenger receptor expression in response to cytokines is
cell-specific. TNF- and IFN-
increased scavenger receptor
activity and mRNA in rabbit vascular smooth muscle cells (39) .
TGF-
, in combination with other cytokines, increased scavenger
receptor activity in rabbit smooth muscle cells(40) . The
mechanism for the divergent effects of these cytokines on these two
cell types (macrophages and smooth muscle cells) is unknown. However,
it may reflect the fact that basal level of scavenger receptor
expression in these two cell types is markedly different. Macrophages
constitutively express macrophage scavenger receptor, whereas smooth
muscle cells express little or no scavenger receptor mRNA or protein
unless induced by cytokines, growth factors, or
PMA(39, 40) . (
)
Macrophage scavenger
receptor mRNA steady state levels in THP-1 monocytes were up-regulated
by the addition of PMA; however, TNF- decreased macrophage
scavenger receptor mRNA steady state levels to about 30% of THP-1
macrophages (Fig. 4, A and B). Two isoforms of
macrophage scavenger receptor, types SR-AI and SR-AII, on human
macrophages (including PMA-differentiated THP-1 macrophages) are
encoded by a single gene that gives rise to an alternatively spliced
primary transcript(41, 42, 43) . To further
determine the effect of TNF-
on the differential expression of the
macrophage scavenger receptor gene subtypes, RT-PCR amplification for
human macrophage scavenger receptor types SR-AI and SR-AII in
PMA-differentiated THP-1 macrophages was performed. We found that
TNF-
destabilizes the expression of both macrophage scavenger
receptor isoforms (SR-AI and SR-AII) during the differentiation of
THP-1 monocytes to THP-1 macrophages (Fig. 4C).
Glass and his colleagues have studied transcriptional regulation of the macrophage scavenger receptor gene in PMA-differentiated THP-1 macrophages(8, 28, 44) . They have identified transcription factor binding sites for AP-1, SP-1, and ets in the promoter of macrophage scavenger receptor gene from THP-1 macrophages(8) . Furthermore, the mechanisms for developmental regulation and cell-specific expression of macrophage scavenger receptor gene have been investigated. Complicated growth- and differentiation-related regulatory pathways of macrophage scavenger receptor gene transcription in THP-1 macrophages have been proposed(28, 44) . Specifically, positive transcriptional control of the macrophage scavenger receptor is dependent on the combinatorial interactions of multiple positive factors (including Spi-1/PU.1, which binds to the region I, and a ternary complex of c-Jun, JunB, and an ets2-like protein, which binds to the region IV) and negative factors (undefined inhibitory elements, which bind to the regions II, III and VI)(44) . Moreover, the ternary complex binding to the region IV is a target for transcriptional activation following stimulation of THP-1 monocytes with PMA.
Decreased expression of macrophage scavenger receptor mRNA
in response to TNF- resulted, in part, from decreased
transcriptional activity of macrophage scavenger receptor gene.
Specifically, PMA increased macrophage scavenger receptor mRNA in THP-1
monocytes via the transcriptional activation of the macrophage
scavenger receptor gene as shown (Fig. 5) and as
described(44) . TNF-
reduced macrophage scavenger receptor
gene transcription by 20% (Fig. 5). TNF-
has been show to
decrease the transcriptional rate of many
genes(45, 46, 47) . However, other genes are
induced in response to TNF-
mediated by the induction of
transcription factors such as NF
B, AP-1, IRF-1, and
NF-GMa(48) . Whether the effect of TNF-
on transcriptional
down-regulation of macrophage scavenger receptor mRNA alters the
combinatorial interactions of positive and negative factors as
described (44) remains to be further investigated.
Our
results demonstrate that in the presence of actinomycin D (an inhibitor
of transcription), TNF- inhibited macrophage scavenger receptor
mRNA principally by reducing macrophage scavenger receptor mRNA
half-life (Fig. 6). Although both IFN-
(5, 6) and TGF-
1 (7) inhibited
macrophage scavenger receptor mRNA steady state levels, it was
undetermined if these cytokines reduced macrophage scavenger receptor
transcription or if the reduction in mRNA steady state levels was due
to increased mRNA degradation. The TNF-
reduction in macrophage
scavenger receptor mRNA half-life was inhibited by cycloheximide,
implying that new protein synthesis was necessary and suggesting that
TNF-
induced expression of protein(s) that accelerated macrophage
scavenger receptor mRNA degradation (Fig. 7). A reduction of
endothelial cell nitric oxide synthase mRNA half-life has also been
demonstrated in response to TNF-
(49, 50, 51) and was dependent on protein
synthesis(49) .
To assess the effects of TNF- on
cholesterol trafficking in THP-1 macrophages, the role of TNF-
in
macrophage scavenger receptor-mediated CE metabolism was characterized
by evaluating parameters in the CE cycle. TNF-
decreased ACAT
activity (Fig. 8A) and esterification of free
cholesterol (Fig. 8B) by 65% as compared with untreated
cells and paralleled the decrease in aLDL binding. Decreased ACAT
activity most likely resulted from decreased substrate (e.g. cholesterol) availability to the enzyme. However, we cannot rule
out the possibility that decreased ACAT activity in response to
TNF-
may occur through phosphorylation of ACAT by protein
kinase(52) . CE hydrolytic enzymes such as acid CE hydrolase
and neutral CE hydrolase activities were unaffected by TNF-
treatment.
These findings may have physiologic significance in the
pathogenesis of atherosclerosis. Scavenger receptors are expressed by
macrophages in atherosclerotic lesions and are believed to mediate the
binding and uptake of modified LDL including oxidized LDL. Cytokines
produced by cells comprising the atheroma (macrophages, endothelial
cells, smooth muscle cells, and lymphocytes) modulate macrophage
scavenger receptor expression in vitro and are thought to
participate in modulating expression in vivo. The expression
of TNF- is increased in atherosclerotic tissue (53, 54) in comparison with normal vascular tissue.
TNF-
within the atherosclerotic lesion could have a modulatory or
inhibitory effect on macrophage scavenger receptor-mediated
accumulation of oxidized lipoprotein by macrophages. We have previously
demonstrated that TNF-
can up-regulate expression of the LDL
receptor by HepG2 cells (55) by increasing LDL receptor gene
transcription. This study and our previous work (55) demonstrate how cytokines can modulate transcriptional and
post-transcriptional regulation of lipoprotein receptors. These
regulatory effects may potentially alter lipoprotein metabolism in
vascular and hepatic tissues and alter pathophysiologic processes.