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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4796-4802
Retinoic Acid Inhibits Monocyte to Macrophage Survival and
Differentiation
By
Marina Kreutz,
Jana Fritsche,
Ute Ackermann,
Stefan W. Krause, and
Reinhard Andreesen
From the Department of Hematology and Oncology, University of
Regensburg, Regensburg, Germany.
 |
ABSTRACT |
Vitamin A metabolites are potent differentiation-inducing agents for
myelomonocytic cell lines in vitro and are successfully used for the
treatment of patients with acute promyelocytic leukemia. However,
little is known about the effects of vitamin A on normal hematopoietic
cells. Therefore, we investigated the effect of vitamin A on
differentiation and activation of human blood monocytes (MO). Culturing
MO for up to 4 days with 9-cis retinoic acid (RA) and all-trans RA but
not retinol reduced MO survival, with the remaining cells being
morphologically comparable to control cells. Because macrophage
colony-stimulating factor (M-CSF) is a well-known survival factor for
MO, we measured the M-CSF content of MO culture supernatants using
enzyme-linked immunosorbent assay and found that RA suppressed the
constitutive secretion of M-CSF. Northern analysis showed that the
M-CSF mRNA expression was only slightly reduced by RA treatment,
suggesting regulation on the posttranscriptional level. In contrast to
MO, M-CSF secretion by MO-derived macrophages (MAC) was not altered by
RA, suggesting a differentiation-dependent switch in the responsiveness
of MO/MAC to RA. Because M-CSF is not only a
survival-promoting but also a differentiation-promoting factor for myeloid cells, we analyzed the effect of RA on MO to MAC
maturation. RA suppressed the expression of the maturation-associated antigen carboxypeptidase M (CPM)/MAX.1 at both the protein and mRNA
levels and modulated the lipopolysaccharide-stimulated
cytokine secretion of MO/MAC. The addition of exogenous M-CSF to
RA-containing MO cultures fails to overcome the RA-induced inhibition
of MO differentiation. However, the survival rate was improved by
exogenous M-CSF. We conclude that RA acts via two different mechanisms
on monocyte survival and differentiation: posttranscriptionally by controlling M-CSF secretion, which decreases MO survival, and transcriptionally regulating the expression of
differentiation-associated genes. The regulation of M-CSF production
may contribute to the antileukemic effect of RA in vivo by reducing
autocrine M-CSF production by leukemic cells.
| |
INTRODUCTION |
RETINOIC ACID (RA) exerts pleiotropic
effects on cellular growth and differentiation. It induces the
differentiation of promyelocytic HL-60 cells and primary human leukemia
cells into granulocytes1,2 and induces complete remission
in patients with acute promyelocytic leukemia.3 The
biological effects of RA are mediated through intracellular RA
receptors, which are members of the nuclear receptor superfamily,
including receptors for steroid hormones, thyroid hormones, and
retinoids. They function as ligand-inducible transcription factors and
activate target genes after binding as homodimers or
heterodimers.4,5 Suppression of the endogenous RA receptor in a multipotent hematopoietic cell line by a dominant negative RA
receptor blocked neutrophil differentiation at the promyelocyte stage,
suggesting a crucial role for RA/RA receptors in the terminal differentiation of neutrophils.6 Primary human bone marrow or embryonic fetal liver cells as hematopoietic precursors show a shift
to granulocytic differentiation when cultured in the presence of
RA.7,8 Conflicting reports have been published regarding the effects of RA on monocytic differentiation. In the promyelocytic cell line HL-60, RA inhibited monocytic differentiation,9
whereas, in the monoblastic cell line U937, RA was shown to modulate
macrophage differentiation either positive or
negative.10,11 We were interested in the effects of RA on
primary human blood monocytes (MO) and MO-derived macrophages (MAC). MO
differentiation into MAC in vitro is a well-established model system
for a similar differentiation process in vivo.12,13 When MO
are cultured in the presence of serum, characteristic changes in the
morphology, antigenic phenotype, and functional competence of MO occur.
Maturation-associated antigens, such as carboxypeptidase M
(CPM)/MAX.1, CD16, CD51, or CD71, can serve as
differentiation markers to define successful maturation in primary
cultures of human MO.14-18 The signals inducing MO to MAC
differentiation in vitro and in vivo are not well characterized. However, macrophage colony-stimulating factor (M-CSF) is an important cofactor for the survival and differentiation of MO and hematopoietic precursor cells.19,20
We investigated whether RA would influence human MO to MAC maturation
and found that RA inhibited the MO maturation process, followed by the
expression of differentiation-associated markers such as CPM or CD71.
In addition, the survival rate of MO was reduced, which could be
explained by a reduction of the constitutive M-CSF production. Cell
survival but not differentiation could be rescued by the addition of
exogenous M-CSF, suggesting that RA acts not only by the suppression of
endogenous M-CSF.
| |
MATERIALS AND METHODS |
Cell separation and culture.
Peripheral blood mononuclear cells (MNC) were obtained by leukapheresis
of healthy donors, followed by density gradient centrifugation over
Ficoll/Hypaque. MO were isolated from MNC by counter-current elutriation (J6M-E Beckmann centrifuge) using a large-volume chamber (50 mL), a JE-5 rotor at 2,500 rpm, and a flow rate of 110 mL/min in
Hank's balanced salt solution supplemented with 6% autologous human
plasma.17 Elutriated MO were greater than 90% pure as determined by morphology and expression of the MO antigen CD14. Purified MO were cultured on teflon foils (Biofolie 25; Heraeus, Hanau,
Germany) for up to 7 days at a cell density of 106 cells/mL
in RPMI 1640 (Biochrom, Berlin, Germany) supplemented with antibiotics
(50 U/mL penicillin and 50 mg/mL streptomycin; GIBCO, Berlin, Germany),
L-glutamine (2 mmol/L; GIBCO), and 2% pooled human AB-group serum with
or without 9-cis-RA (kindly provided by Hoffmann-La Roche, Basel,
Switzerland), all-trans RA, 13-cis-RA, or retinol (Sigma, St Louis,
MO). Cultures containing RA were fed with half of the
initial RA dose after 2 days. At the indicated time periods, cells were
harvested and viable cells were counted by trypan blue exclusion.
Supernatants of these cultures were also harvested, sterile filtered,
and stored at  20°C for M-CSF determination.
Supernatants of MO/MAC.
Either freshly isolated MO or MAC cultured for 7 days on teflon foils
were cultured at a cell density of 106 cells/mL on petri
dishes for 48 hours plus serum with or without RA. Supernatants were
harvested, sterile filtered, and stored at 20°C for M-CSF
determination.
Detection of M-CSF, interleukin-6 (IL-6), and tumor necrosis
factor- (TNF-).
Cytokines were measured by commercially available enzyme-linked
immunosorbent assay (ELISA) kits (Biermann, Bad Nauheim, Germany).
Flow cytometry.
MAC were harvested on day 4 and washed twice with cold
phosphate-buffered saline (PBS) containing 0.1% sodium azide and 0.6 mg/mL Ig. Cells (5 × 105) were incubated with
saturating amounts of specific monoclonal antibodies or IgG isotype
control for 30 minutes at 4°C. The following antibodies were used:
CD11c, CD14, CD51, CD54, and CD71 from Immunotech (Hamburg, Germany)
and CPM/MAX.1 from our own laboratory. After two further washes, cells
were incubated with saturating concentrations of fluorescein
isothiocyanate-conjugated goat antimouse IgG for 30 minutes at 4°C.
After two more washes, cells were fixed with 1% paraformaldehyde in
PBS. Analysis was performed using a FACScan (Becton Dickinson, Mountain
View, CA). Cell populations were gated according to their
forward and side scattering. The same instrumental setting (FL1 426)
was used for MAC cultured with or without RA.
RNA extraction and Northern analysis.
MAC were harvested from the teflon foils and lysed with guanidine
thiocyanate solution. RNA extraction was performed according to
Chomczynski and Sacchi.21 Ten micrograms of total RNA was run in 1% agarose-formaldehyde gels and transferred to nylon membranes (NT membranes; MSI, Westborough, MA). M-CSF mRNA was
detected by hybridization of the membranes with an oligonucleotide
complementary to bp 275-311 of the published sequence.22
This probe was labeled with T4 polynucleotide kinase and
 -(32P)-ATP (3,000 Ci/mmol; Amersham, Buckinghamshire,
UK). Hybridization conditions were 500 mmol/L sodium phosphate, pH 7.2, 7% sodium dodecyl sulfate (SDS), 1 mmol/L EDTA, and 150 mg/mL tRNA at
56°C overnight. CPM mRNA was detected by hybridization with a
32P-labeled cDNA probe (random primed labeling kit;
Boehringer Mannheim, Germany) of the EcoRI restriction
fragments of the cloned CPM polymerase chain reaction
(PCR) fragment.23 To provide an internal control, membranes were reprobed with an oligonucleotide against 18 S
rRNA labeled by T4 kinase.
| |
RESULTS |
Effect of RA on MO survival.
MO were cultured for up to 4 days on teflon foils with or without
10 7 mol/L 9-cis-RA, harvested, and counted. Cell
numbers are given as the percentage of cells of the starting
population. We found that, compared with cells cultured without RA, the
survival rate of cells cultured with RA was reduced 25% ± 7%
(mean ± SEM; n = 10) on day 2 and 36% ± 5% (mean ± SEM; n = 17) on day 4 (Fig 1). However, the
morphology of the remaining cells resembled MAC from cultures free of
RA.
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| Fig 1.
Comparative analysis of MO survival, secreted M-CSF
protein, and M-CSF mRNA level after RA treatment. MO were cultured for 2 days and 4 days, respectively, on teflon foils with or without 107 mol/L RA. Cells were harvested, counted, and lysed
with guanidine thiocyanate solution. Northern analysis was performed as
described in the Materials and Methods. Densitometric analysis of the
signals was performed. M-CSF content of the corresponding supernatants was determined by ELISA. All values are given as the mean percentage of
inhibition by RA compared with the serum control (results are significantly different: for survival, day 2 [P < .02] and
day 4 [P < .0001]; for M-CSF protein, day 2 [P < .03] and day 4 [P < .009]; for M-CSF mRNA, day 4 [P < .05] by two-tailed t-test for paired data).
Results are not significantly different for day 2 mRNA data.
|
|
Regulation of M-CSF secretion by RA.
Because M-CSF is a potent survival and differentiation factor for human
MO, we analyzed whether a reduction of M-CSF protein in the
corresponding culture supernatants would explain the decreased survival
rate of MO/MAC cultured with RA. Therefore, we measured the M-CSF
content in the supernatant after 2 days and after 4 days and found an
average reduction of M-CSF in the culture supernatant of 49% ± 9%
(mean ± SEM; n = 11) on day 2 and 61% ± 7% (mean ± SEM; n = 17) on day 4 as compared with the control (Fig 1). Five experiments
in which survival, M-CSF protein, and M-CSF mRNA were analyzed in
parallel are shown in Table 1. A decrease
in MO/MAC survival was always paralleled by a decrease in the M-CSF
level of the corresponding supernatant; however, the absolute M-CSF value varied between different donors and did not correlate with the
survival rate of MO/MAC. This indicates that other mechanisms, eg, at
the M-CSF receptor level, may influence MO/MAC survival.
Because adherence is a strong inducer of M-CSF mRNA expression and
protein synthesis, we were interested as to whether this downregulation
would also take place on plastic surfaces, because teflon is only a
weak adherence substrate for MO/MAC. Freshly isolated MO were cultured
for 48 hours on petri dishes with or without different RA isomers.
Control MO were incubated with retinol, the inactive precursor of RA.
As shown in Fig 2, at a concentration of
107 mol/L, all RA metabolites could reduce M-CSF
protein secretion, even on plastic surfaces, whereas retinol had no
effect. RA at a concentration of 109 mol/L had a
slight effect on the reduction of M-CSF protein in the supernatant;
however, no effect was found on the survival rate or antigen expression
(data not shown). Interestingly, M-CSF production of MO-derived MAC was
not inhibited by RA, indicating a differentiation-dependent switch in
the responsiveness of MO/MAC to RA. Addition of exogenous M-CSF to
RA-containing cultures resulted in a cell survival rate comparable to
that of the controls (data not shown).
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| Fig 2.
M-CSF secretion is decreased by different RA metabolites
in MO but not in MO-derived MAC. Either MO or MO-derived MAC were cultured for 48 hours with or without serum plus 107
mol/L 9-cis-RA, all-trans-RA, 13-cis-RA, or retinol on petri dishes.
The M-CSF content of these supernatants was analyzed by ELISA.
|
|
Effect of RA on M-CSF mRNA expression.
RA is known to regulate gene expression via binding to its
intracellular receptors acting as transcription factors. Therefore, we
investigated whether the inhibition of M-CSF production would correspond to a reduced expression of M-CSF mRNA. RNA was isolated from
MO cultured for 2 days and 4 days with serum plus RA and analyzed by
Northern analysis. Freshly isolated MO showed no expression of the
M-CSF mRNA (data not shown), but after 2 and 4 days of adherence
culture, a signal could be detected. RA did not reduce the expression
of M-CSF mRNA in day-2 cultures, indicating a posttranscriptional regulation of M-CSF production (Fig 3);
however, on day 4, the mRNA was slightly reduced by 26% (Fig 3 and
Table 1, experiment no.1). In 4 of 8 experiments, we could detect a
decrease of the M-CSF mRNA on day 4 (control v RA, different
with P < .05); however, only 1 of 8 experiments showed a
slight reduction of M-CSF mRNA on day 2 (no significant difference).
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| Fig 3.
M-CSF expression on mRNA level is only slightly altered
by RA treatment. RNA was isolated from MO cultured for 2 days or 4 days
on teflon foils with or without 107 mol/L RA. Northern
analysis was performed according to the Materials and Methods.
Hybridization with an 18S rRNA oligonucleotide is shown as a loading
control.
|
|
Maturation-associated antigen expression is altered by RA.
M-CSF is not only a survival but also a differentiation promoting
factor for myeloid cells. Therefore, we analyzed whether RA would also
modulate MO differentiation. MO were cultured for 4 days on teflon
foils with or without 107 mol/L 9-cis-RA and the
expression of maturation-associated antigens was followed by flow
cytometry. Figure 4 shows a comparison of the antigen expression of MO-derived MAC cultured with or without RA
regarding the expression of MAX.1/CPM and CD14. The expression of CPM,
which is normally nearly undetectable on freshly isolated MO and
upregulated during the differentiation of MO to MAC, remained low in
RA-containing cultures, whereas the expression of CD14 was comparable
to control cultures. Expression of other differentiation-dependent antigens such as CD51 and CD71 were also suppressed by RA. In contrast,
HLA-DR expression was upregulated by RA
(Fig 5). Because RA had no effect
on the M-CSF mRNA level, despite a suppression of the protein level, we
investigated whether this is also true for CPM expression. Similar to
the protein level, CPM mRNA level declined in a dose-dependent manner
after RA incubation (Fig 6).
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| Fig 4.
RA suppresses CPM expression but not CD14 expression in
MAC. MO were cultured on teflon foils in serum with or without
107 mol/L 9-cis-RA. After 4 days, cells were harvested
and stained according to the Materials and Methods for flow
cytometry.
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| Fig 5.
Effect of RA on antigen expression analyzed by flow
cytometry. MO were cultured on teflon foils with or without
107 mol/L 9-cis-RA. After 4 days, cells were harvested
and stained according to the Materials and Methods. Data represent the
difference in fluorescence intensity between cultures with or without
RA (mean ± SEM for at least 3 experiments with different donors).
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| Fig 6.
CPM expression is also suppressed on mRNA level by RA.
Total RNA was isolated either from MO cultured on teflon foils with 107 mol/L 9-cis-RA (lane 2) or 109 mol/L
9-cis-RA (lane 3) or without RA (lane 1). After 4 days cells were
harvested and Northern analysis was performed according to the
Materials and Methods. Hybridization with an 18S rRNA oligonucleotide is shown as a loading control.
|
|
Cytokine secretion is modulated by RA.
Besides the morphology and antigen-expression, the functional activity
of MO changes during the differentiation into MAC. Especially the
lipopolysaccharide (LPS)-induced cytokine production can serve as a
maturation marker for MO-derived MAC. We therefore analyzed whether MO
cultured with or without RA would differ in their ability to produce
IL-6 and TNF- after LPS stimulation. Control MAC cultured in the
presence of serum showed a normal MAC LPS response, ie, a high
secretion of TNF- and a low secretion of IL-6. However, MAC derived
from RA-containing cultures showed an inverse pattern of cytokine
secretion after LPS stimulation (Fig 7)
that is a typical feature of freshly isolated MO, indicating that MO do
not differentiate into functionally normal MAC in the presence of RA.
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| Fig 7.
MAC cytokine pattern is modulated by RA. MO were cultured
on teflon foils with or without 107 mol/L 9-cis-RA.
After 4 days, cells were harvested, seeded in a 6-well plate at a
density of 5 × 105/mL, and stimulated for another 24 hours with 100 ng/mL LPS. Cytokines were determined by ELISA.
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| |
DISCUSSION |
RA is a well-known inducer of the differentiation of promyelocytic cell
lines1 and primary leukemic cells in vitro.2,24 However, little is known about the effect of RA on the differentiation and activation of normal human hematopoietic cells. For the first part
of MO differentiation, the development of MO from hematopoietic precursor cells, RA has been shown to shift the differentiation to the
granulocytic pathway.7,8 In this study, we were interested whether RA modulates the next step of MO maturation, the
differentiation of normal human blood MO into MAC. To analyze the
effects of RA on MO/MAC maturation, MO were cultured with serum as the
usual inducer of MO differentiation in vitro with or without RA.
Morphology of MAC was not influenced by RA treatment, but the
functional activity and the expression of maturation-associated
antigens, such as MAX.1/CPM, CD51, and CD71, were suppressed.
Accordingly, Northern analysis showed a reduction of the CPM mRNA
level. The effect of RA on MO/MAC differentiation has also been studied
by others, including the differentiation of the human monoblastic cell
line U937 and the differentiation of osteoclasts in
chicken.11,25 Both studies found an antagonistic effect of
1,25-dihydroxyvitamin D3
[1,25(OH)2D3] and RA on the differentiation
process, with RA being dominant over
1,25(OH)2D3.
1,25(OH)2D3, which is a potent inducer of MO differentiation,26,27 could also not overcome the differentiation block by RA in our system (data not shown). The
functional antagonism of RA and 1,25(OH)2D3 on
MAC differentiation may be explained by an interaction of RA receptors
(RAR and RXR) and 1,25(OH)2D3 receptors (VDR).
Heterodimers of these receptors can act as transcription factors
regulating the expression of different genes.28 The
regulation is dependent on the receptor level and the ligand
concentration. In vitro, it has been shown that an excess of 9-cis-RA,
a ligand for the RAR and the RXR receptor, destabilizes the VDR/RXR
heterodimer, leading to an inhibition of
1,25(OH)2D3-activated gene
expression.29,30 In our system, not only 9-cis RA but also
all-trans RA, which binds to another RA receptor, RAR, suppressed
maturation, indicating additional mechanisms of action. Cao et
al31 reported that VDR/RXR and RAR/RXR heterodimers can
compete for a shared half site in the response element for the integrin
V 3/CD51 (which was also suppressed during
MO differentiation in the presence of RA). Co-addition of both ligands,
1,25(OH)2D3 and RA, completely inhibited the transactivational effect of
1,25(OH)2D3.31 But RA receptors do
not only interact with just VDR but also with other transcription factors such as AP-1. The expression of the
AP-1-responsive gene collagenase, which is also a maturation marker
for MO/MAC, is downmodulated by the RA receptor RAR.32
Therefore, we suggest that the interactions of RA receptors with other
transcription factors that are involved in the regulation of
differentiation may lead to a differentiation block in MO/MAC.
Besides the changes in functional activity and antigen expression, the
addition of RA to MO cultures leads to a decrease in the survival rate
of MO, which could be explained by a reduction of the M-CSF content in
RA-containing cultures because M-CSF is a well-known survival factor
for MO.19,20 Accordingly, survival was comparable to
control cultures after supplementation of RA-containing cultures with
exogenous M-CSF. In contrast to our findings, Nakajima et
al33 reported an increase in the M-CSF production in
primary cultures of human bone marrow stromal cells and in a human bone marrow stromal cell line cultured with RA.33 Similar
results were found by Hamilton et al34 with synovial
fibroblasts. This discrepancy may be due to the fact that different
cell types were studied. In MAC, which are also a part of the bone
marrow stroma, we were not able to find a downregulation of M-CSF
production. The differences in the responsiveness of cells to RA can be
explained by differences in the receptor level or concentrations of
cellular RA binding proteins (CRABP) in the target cell. Preliminary
results in our laboratory suggest that the unresponsiveness of MAC
could be due to a high expression of CRABP II, which can inhibit RA action (data not shown). Freshly isolated MO showed no expression of
the M-CSF mRNA on the mRNA level (and no protein was detected in the
corresponding supernatant), but after 24 to 48 hours, a strong signal
could be detected that was similar with or without RA, ie, the
reduction in M-CSF protein levels was not paralleled by a decrease in
the mRNA level. However, after 96 hours, a slight reduction was also found on mRNA level. Accordingly, Haskill et al35 found an induction of M-CSF mRNA by adherence without
further stimulation. Regarding the regulation of the M-CSF mRNA,
similar results have been published by Lee et al,36 who
investigated the regulation of M-CSF by prostaglandin E2
(PGE2) and found that PGE2 not
only inhibited M-CSF protein levels but even upregulated the mRNA.
Therefore, M-CSF seems, at least in part, to be regulated by
posttranscriptional mechanisms.
RA is used in the treatment of acute promyelocytic
leukemia,3 myelodysplastic syndrome,37 and
juvenile chronic myelogenous leukemia.38 Elevated
circulating levels of M-CSF are found in acute myeloid leukemia
(AML) and other leukemias,39,40 ovarian adenocarcinoma,41 and myeloproliferative
disease.42 In addition, the receptor for M-CSF, cfms, is
expressed in AML and other malignancies.41,43 If M-CSF
plays a role as an autocrine or paracrine growth factor in these
diseases, the downregulation of M-CSF may be one explanation for the
therapeutic effects of RA.
| |
FOOTNOTES |
Submitted June 24, 1997;
accepted February 13, 1998.
Supported by DFG.
Address reprint requests to Marina Kreutz, PhD, Department of
Hematology and Oncology, University of Regensburg,
Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany; e-mail:
Marina.Kreutz{at}klinik.uni-regensburg.de.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract