© 1999 American Heart Association, Inc.
Vascular Biology |
9-cis Retinoic Acid Induces Monocyte Chemoattractant Protein-1 Secretion in Human Monocytic THP-1 Cells
From the Department of Vascular and Cardiac Diseases (L.Z., C.L.B., R.S.N.), Parke-Davis Pharmaceutical Research, Ann Arbor, Mich, and The Lipid Research Laboratory (M.A.), Technion Faculty of Medicine, Rambam Medical Center and the Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel.
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Abstract |
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Abstract—Monocyte migration and activation are regulated by monocyte chemoattractant protein-1 (MCP-1). Prior studies have shown MCP-1 expression is modulated by a variety of ligands that act through extracellular receptors. In the current study, we show 9-cis retinoic acid (RA), a ligand for the nuclear hormone receptor retinoid X receptor (RXR) and retinoic acid receptor (RAR), markedly induces the expression of MCP-1. In human THP-1 monocytic leukemia cells cultured with RA (0.05 to 500 nmol/L), MCP-1 expression was induced rapidly, significantly, and dose-dependently by as much as 165-fold. MCP-1 RNA level was also increased in RA-treated cells. Expression of PPAR
, a heterodimer partner of RXR, is also
markedly induced by RA in THP-1 cells. However, BRL49653, a PPAR
ligand, failed to induce MCP-1 secretion either alone or to modify the
expression level induced by RA. In contrast, BRL49653 significantly
increased MCP-1 (biotinylated MCP-1) binding to THP-1 cells, whereas RA
had no effect. Other peroxisome proliferator activated receptor
(PPAR) ligands, 15d-PGJ2 and troglitazone (PPAR),
Wy14,643 (PPAR
), and PD195599 (PPARß) inhibited the induction of
MCP-1 by RA. RA's effect on MCP-1 expression in human elutriated
monocytes were similar to that observed in the THP-1 cells. These
studies identify RA as a nuclear signal for MCP-1 induction in
undifferentiated human monocytic cells. These studies also suggest
monocyte MCP-1 expression induced through RA may modulate cell
migration.
Key Words: PPAR • MCP-1 • nuclear hormone receptor • monocyte migration • CCR2 • ELISA • RNase protection assay
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Introduction |
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Monocyte chemoattractant protein-1 (MCP-1) belongs to the ß or C-C subfamily of chemotactic cytokines, also known as the chemokines (or intercrines).1 2 The expression of this 76-amino acid monomeric protein3 4 5 6 has been detected in various human diseases, including atherosclerosis,7 8 9 skin delayed-type hypersensitivity reactions,10 cancer,11 rheumatoid arthritis,12 and renal failure.13 MCP-1 has largely been associated with modulating monocyte migration in response to inflammation.4 MCP-1 has been shown to induce Ca++ flux, integrin and tissue factor expression, arachidonic acid release, and cytokine expression in monocytes.4 14 15 16 17 18 19 MCP-1 has also been shown to stimulate basophils to release histamine20 and a subset of lymphocytes to migrate.21 22 Recently, additional functions of MCP-1 have been revealed, including blockage of M-tropic virus entry into blood dendritic cells23 and protection of mice from lethal endotoxemia.24 In this regard, MCP-1 induction may be of clinical relevance.
MCP-1 expression is induced in a wide variety of cells in vitro,
including monocytes, fibroblasts, and vascular
endothelial and smooth muscle cells, in response to
various extracellular stimuli such as tumor necrosis factor-,
leukemia inhibitory factor, IL-1, IL-4, IL-6, IL-15,
lipopolysaccharide (LPS), platelet-derived growth factor,
or interferon-.1 25 26 27 28 29 30 31 32
In contrast to extracellular ligands, Burn et al33 has shown that all-trans retinoic acid (ATRA), a ligand for retinoic acid receptor (RAR)34 also elevates expression of MCP-1 in human HL-60 and NB4 cells. RAR is a member of the nuclear hormone receptor superfamily. On ligand activation, RAR modulates the expression of its target genes by binding to specific DNA elements in their promoter regions.35 ATRA also promotes the differentiation of HL-60 and NB4 cells to neutrophil-like cells. Thus, whether increased MCP-1 expression is a direct effect of ATRA or a consequence of differentiation in those studies is unknown. In this regard, these investigators have also shown that MCP-1 expressed in human peripheral blood neutrophils is not further induced by ATRA.33
To examine the regulation of MCP-1 expression in undifferentiated human
monocytes, human THP-1 cells, which highly express retinoid X receptor
(RXR)36 were cultured with 9-cis retinoic acid
(RA). RA activates signaling pathways through RXR-RXR
homodimers,37 38 and both liver X receptor-RXR
(LXR-RXR)39 and PPAR-RXR
heterodimers.40 41 42 RA has also been shown to induce
PPAR expression in undifferentiated THP-1 cells.43 It
has recently been reported that PPAR plays an important regulatory
role in monocyte and macrophage inflammatory
actions,44 45 as well as in lipid-laden foam cell
transformation.46 47 In the current study, RA was used to
examine whether the retinoic acid signaling pathway regulates MCP-1
expression in THP-1 cells as well as in monocytes isolated from human
blood. Our data indicates RA may act as a nuclear signal for induction
of MCP-1 expression.
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Methods |
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Chemicals
RA was purchased from Sigma Chemical Co. Wy 14,643 was purchased from Chemsyn Science Laboratory. 15d-PGJ2 was purchased from Cayman Chemical Company. BRL49653, troglitazone, and PD195599 {4-(3-(2-propyl-3-hydroxy-4-acetyl-phenoxy)propyloxy)-phenoxy acetic acid, Merck compound A}48 were synthesized at Parke-Davis Pharmaceutical Research, Ann Arbor, MI.
Cell Culture
Human THP-1 cells were obtained from the American Type Culture
Collection, Manassas, VA. Cells were cultured in RPMI 1640
medium (Gibco BRL) containing 10% fetal bovine serum and 0.05
mmol/L 2-mercaptoethanol (Gibco BRL). For RA and PPAR ligands
treatments, cells (1x105 cells/mL) were switched
to differentiation medium (DM) containing 1% Nutridoma-Hu
(Boehringer Mannheim) and 0.05 mmol/L 2-mercaptoethanol in
RPMI 1640 medium containing the ligands in dimethylsulphoxide (DMSO;
0.2% of final volume). Frozen elutriated human monocytes (Advanced
Biotechnologies Inc, Md) were thawed, plated at
1x105 cells/mL and cultured for 1 day in RPMI
1640 medium (Gibco BRL) containing 20% fetal bovine serum. DMSO, RA,
or BRL49653 were then directly added to the culture medium.
Migration Assay
THP-1 cell migration assay was performed using 6.5-mm Costar
Transwell cell culture chamber49 with polycarbonate
membrane (5.0 micron pore) following the manufacturer's protocol.
MCP-1 protein (R&D Systems, Minneapolis, Minn) was dissolved in
RPMI1640 medium with 0.2% BSA and placed in lower compartment.
THP-1/F4-2 cell suspensions of 7x105 cells/mL in
RPMI1640 medium with 0.2% BSA were first treated with either DMSO
vehicle control or 500 nmol/L RA for 12 hours and then loaded in the
upper compartment. After 3-hour incubation at 37°C in a humidified
atmosphere with 5% CO2, the number of cells
migrated to the lower compartment was counted with Coulter Z1 particle
counter.
RNase Protection Assays
Total cellular RNA was isolated from THP-1 cells treated with RA
for 24 hours using TRIzol reagents (Gibco BRL). A
32P-labeled antisense riboprobe for human MCP-1
was prepared using a RiboQuant In vitro Transcription Kit (PharMingen)
with the hCK-5 RiboQuant Human Cytokine Multi-Probe Template
Set (PharMingen), which contains the DNA template for human MCP-1 cDNA.
A 32P-labeled antisense riboprobe for human MCP-1
receptor (CCR-2) was prepared using the RiboQuant In vitro
Transcription Kit with the hCR-5 RiboQuant Human Cytokine
Multi-Probe Template Set (PharMingen) which contains the DNA templates
for human CCR-2a and CCR-2b cDNA. RNase protection assays were
performed using an Ambion RPA II RNase protection assay kit (Ambion).
RNase protection results were quantified by NIH Image version 1.61.
MCP-1 ELISA
The concentration of MCP-1 released into the medium was
determined by ELISA of culture supernatants. MCP-1 protein was measured
with a Quantikine Human MCP-1 Immunoassay ELISA kit (R&D Systems)
following the manufacturer's protocol. Data were analyzed
using SOFTmax PRO software (Molecular Devices).
Biotinylated MCP-1 Binding Assay
MCP-1 binding assays were performed using FLUROKINE Human MCP-1
Biotin Conjugate Flow Cytometry Reagents (R&D Systems) according to the
manufacturer's protocol. Briefly, treated THP-1 cells were washed
twice with Dulbecco's PBS (w/o Ca2+,
Mg2+) and then stained with biotinylated Human
MCP-1. Biotinylated soybean trypsin inhibitor, supplied
with the kit, was used as a negative control. Cells were then treated
with avidin-fluorescein and analyzed by flow
cytometry on a FACScan (Becton Dickinson). Data were analyzed
with CellQuest software (Becton Dickinson).
Statistical Methods
All data were expressed as mean±SD. Statistical significance
was determined with Tukey's multiple comparison procedure applied
after a one-way ANOVA conducted on data. The level of statistical
significance for all tests was P<0.05.
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Results |
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Regulation of MCP-1 expression by the retinoic acid signaling pathway was examined in human monocytic THP-1 cells cultured with RA. Cells treated with RA (0.05 to 500 nmol/L) for 24 hours released MCP-1 into the medium in a concentration-dependent manner reaching a 165-fold increase at the highest concentration of RA tested (Figure 1A
). MCP-1 induction was rapid, indicated
by a substantial increase of MCP-1 in culture medium after only 2 hours
following 500 nmol/L RA addition (Figure 1B).
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MCP-1 RNA was also induced in the RA-treated THP-1 cells. After 24
hours, RA treatment caused a concentration-dependent and dramatic
induction of MCP-1 RNA (6.7-fold induction in 5 nmol/L RA-treated cells
and 12.4-fold induction in 500 nmol/L RA-treated cells) as revealed by
a RNase protection assay (Figure 2).
Under these conditions, THP-1 cells do not differentiate into
macrophages.43
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To determine whether MCP-1 induction was dependent on ligand
interaction with PPAR, THP-1 cells were exposed to DMSO vehicle, or
1 or 10 µmol/L BRL49653 (a ligand for PPAR) in the presence
or absence of 500 nmol/L RA (Figure 3).
BRL49653 failed to induce MCP-1 secretion alone and did not
significantly alter the response observed after RA treatment. Although
reduced MCP-1 secretion was observed at 10 µmol/L BRL49653,
significance was not achieved. Additional PPAR ligands were also tested
to determine whether they could modulate RA induction of MCP-1.
THP-1 cells were cultured with 3 µmol/L
15d-PGJ2,46 15 µmol/L troglitazone
(PPAR ligands),46 100 µmol/L
Wy14,64350 45 (PPAR ligand), or 20 µmol/L
PD19559948 (PPARß ligand) in the absence (Figure 4A) or presence of 500 nmol/L RA (Figure 4B).
In the absence of RA, 15d-PGJ2,
troglitazone, and PD195599 significantly decreased, whereas Wy14,643
slightly increased the MCP-1 secretion in THP-1 cells. In the presence
of 500 nmol/L RA, all 4 PPAR ligands inhibited the induction of MCP-1
secretion.
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Human biotinylated MCP-1 binding was used to estimate whether RA or
BRL49653-treated cells increase the expression of MCP-1 cell surface
receptors.51 As shown by flow cytometry, RA (5 or 500
nmol/L)-treated THP-1 cells showed no change in MCP-1 binding (Figure 5A). In contrast, BRL49653 (1 or 10
µmol/L)-treated THP-1 cells significantly increased MCP-1 binding
(Figure 5B). Flow cytometry histograms for combinations of RA
(500 nmol/L) with BRL49653 (1 or 10 µmol/L) were essentially the
same as with BRL49653 alone (data not shown). In RA-treated THP-1
cells, a local increase in extracellular MCP-1 may act in an autocrine
manner and cause receptor internalization. An apparent lack of an
effect of RA on MCP-1 cell surface receptor expression may be due to
this antocrine regulation. Indeed, MCP-1 receptor RNA was actually
increased in the RA-treated THP-1 cells (Figure 6).
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Human elutriated monocytes were also assessed for their ability to
produce MCP-1 in response to RA. Cells were treated with DMSO, 500
nmol/L RA, or 10 µmol/L BRL49653 for 12 hours. MCP-1 secretion
was induced (
15-fold) in the RA-treated cells (Figure 7).
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To determine whether RA induction of MCP-1 impeded the chemotactic
response, cell migration assays were performed using CCR-2 (the MCP-1
receptor) preselected THP-1 cells. Without preselection, we observed no
effect of MCP-1 on chemotaxis (data not shown). Similarly, Vaddi et
al52 reported the inability to demonstrate chemotaxis in
unselected THP-1 cells. Therefore, cells were selected for CCR-2 for
migration assays (THP-1/F4-2 subpopulation). In the absence of
exogenous MCP-1, 500 nmol/L RA pretreatment (12 hours) resulted in a
600% inhibition in the ability of the THP-1/F4-2 to migrate to the
lower chamber. Exogenous MCP-1 in the lower chamber resulted in
enhanced migration of the DMSO- or RA-treated THP-1/F4-2 cells.
However, as the concentration of MCP-1 increased in the lower chamber,
the inhibitory effect of RA on migration was mitigated
(Figure 8A). The expression of MCP-1
receptor on the THP-1/F4-2 cell surface was also not affected by the RA
treatment (Figure 8B).
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Discussion |
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MCP-1 plays a critical role in the regulation of human monocyte function; however, the mechanism by which MCP-1 expression is regulated is not fully understood. Although various ligands known to bind cell surface receptors have been shown to induce MCP-1 expression, the nuclear events responsible for increased expression are poorly understood. In the current study, we discovered that RA, a ligand for the nuclear hormone receptor RXR, produces a massive induction of MCP-1 RNA as well as the secreted protein from THP-1 cells. RA also induces PPAR
expression in these cells,43 and this receptor can
heterodimerize with RXR. RXR can also heterodimerize with LXR and form
homodimers. Recently, it was reported that PPAR ligands regulate
monocyte and macrophage in inflammatory
actions.44 45 In the current study, addition of a ligand
to PPAR (BRL 49653) did not alter the MCP-1 expression level
observed with RA alone (Figure 3
). Other PPAR ligands, including
15d-PGJ2 and troglitazone (PPAR ligands),
Wy14,643 (PPAR ligand), and PD195599 (PPARß ligand) inhibited the
RA's induction of MCP-1 secretion (Figure 4B). These data
suggest that the RA induction of MCP-1 expression is not mediated
through PPAR activation. Although MCP-1 expression is similarly induced by PMA, LPS, or RA, MCP-1 binding to the cell surface differs. Both PMA and LPS suppress,32 53 whereas RA has no effect on binding of MCP-1 to monocytes. The THP-1 cells treated with RA secrete MCP-1 and also express the MCP-1 receptor. Therefore, RA treatment may result in an autocrine regulation. Indeed, RNA from RA-treated cells show an increase in MCP-1 receptor RNA despite no detectable increase in MCP-1 cell surface receptors. Interestingly, BRL49653 alone significantly increased the MCP-1 binding to THP-1 cells, although BRL49653 failed to alter MCP-1 expression in this same system. Overall, the data presented demonstrate that MCP-1 function may be differentially regulated by PPAR and RA signaling pathways.
The findings of the current study provide evidence that RA-RXR may be the intracellular/nuclear signaling pathway for MCP-1 induction. Whether extracellular signals that also increase MCP-1 expression act via ligand activation of RXR is currently not known. Inhibition of MCP-1 induction in experiments in which RXR-RA interactions are blocked, by either antagonism or by the creation of a RXR deficiency, may yield direct evidence for the existence of the nuclear pathway.
Markedly enhanced monocyte MCP-1 expression may have functional
relevance. High secretion of MCP-1 could create a localized increased
cytokine concentration, thereby making the monocyte resilient
to concentration gradients that act as chemotactic targeting signals.
Indeed, we demonstrate (Figure 8A) that only very high
concentrations of exogenous MCP-1 could completely override the
suppressive migration effect RA had on THP-1 cells. Perhaps RA
modulates an antichemotactic response, decreasing the infiltration of
monocytes to an inflammatory site. Our finding that blocking of
monocyte migration by RA may have relevance to the recent
reports54 55 showing the roles of MCP-1 and its receptor
in atherosclerosis development. In this regard, animal
models of impaired monocyte migration including the LDL receptor/MCP-1
deficient mouse and CCR2/apoE deficient mouse have each been shown to
significantly quell the progression of atherosclerosis.
Taken together, these data suggest that nuclear ligands that regulate
MCP-1 expression may have therapeutic utility in the treatment of
atherosclerosis diseases.
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Acknowledgments |
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The authors gratefully acknowledge Dr. Sheila Sanders of Parke-Davis for providing THP-1/F4-2 cells. We are also grateful to Mark Yates and Dr. Ed Low also of Parke-Davis for their assistance with the chemotaxis assay.
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Footnotes |
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Drs. Lingyu Zhu and Charles L. Bisgaier are currently at Esperion Therapeutics, Inc., Ann Arbor, Mich.
Received October 7, 1998; accepted March 10, 1999.
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