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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 845-852
Serial Analysis of Gene Expression in Human Monocyte-Derived Dendritic
Cells
By
Shin-ichi Hashimoto,
Takuji Suzuki,
Hong-Yan Dong,
Shigenori Nagai,
Nobuyuki Yamazaki, and
Kouji Matsushima
From the Department of Molecular Preventive Medicine and CREST,
School of Medicine,The University of Tokyo, Tokyo, Japan.
 |
ABSTRACT |
Dendritic cells (DCs) are professional antigen-presenting cells in
the immune system and can be generated in vitro from hematopoietic progenitor cells in the bone marrow, CD34+ cord blood
cells, precursor cells in the peripheral blood, and blood monocytes by
culturing with granulocyte-macrophage colony-stimulating factor
(GM-CSF), interleukin-4, and tumor necrosis factor- . We have performed serial analysis of gene expression (SAGE) in DCs derived
from human blood monocytes. A total of 58,540 tag
sequences from a DC complementary DNA (cDNA) library represented more
than 17,000 different genes, and these data were compared with SAGE analysis of tags from monocytes (Mo) and GM-CSF-induced macrophages (M ). Many of the genes that were differentially expressed in DCs
were identified as genes encoding proteins related to cell structure
and cell motility. Interestingly, the highly expressed genes in DCs
encode chemokines such as TARC, MDC, and MCP-4, which preferentially
chemoattract Th2-type lymphocytes. Although DCs have been considered to
be very heterogeneous, the identification of specific genes expressed
in human Mo-derived DCs should provide candidate genes to define
subsets of, the function of, and the maturation stage of DCs and
possibly also to diagnose diseases in which DCs play a significant
role, such as autoimmune diseases and neoplasms. This
study represents the first extensive gene expression analysis in any
type of DCs.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
DENDRITIC CELLS (DCs) PLAY a pivotal role
in the immune system by processing and presenting antigens to
CD4+ naive T cells.1 DCs have also been
reported to be involved in directly inducing cytotoxic T cell
(CTL), Ig production by B cells, and T-cell tolerance. DCs
in lymphoid and nonlymphoid organs vary in their surface markers and
functions and, therefore, have different names (eg, the Langerhans cell
in the skin; the interdigitating DC in the lymph nodes; the
interstitial DC in heart, lung, kidney, and intestine; and the thymic
DC in the thymus). DCs are thought to belong to a lineage distinct from
monocytes (Mo)/macrophages (M ). However, it has been reported that
M and DCs share a common progenitor.2 Human DCs have
been generated from CD34+ precursor cells isolated from
cord blood3 and bone marrow4 in the presence of
granulocyte-macrophage colony-stimulating factor (GM-CSF)
and tumor necrosis factor- (TNF-). Moreover, blood monocytes
cultured with GM-CSF and interleukin-4 (IL-4) differentiate into
nonadherent CD1a+CD14low/ cells with
morphologic and functional characteristics of DCs.5,6 DCs
become mature DCs expressing CD83 by stimulating with TNF-, CD40
ligand, lipopolysaccharide (LPS),7 or
monocyte-conditioned medium.8 However, the process of
differentiation from monocytes to DCs has not been systematically
explored. In this study, we have applied the recently developed serial
analysis of gene expression (SAGE) method to allow quantitative
analysis of an extremely large number of transcripts in human DCs. The
SAGE method has provided a powerful means for the quantitative
cataloging and comparison of expressed genes in the cells or tissues
from various physiological, developmental, and pathological
states.9-12 This may provide not only useful information to
define the development and function of DCs, but also a greater
understanding of the differentiation pathway and of the immunological
relationship between monocytes/macrophages and DCs by comparison
between SAGE analysis of tags from DCs and from Mo or GM-CSF-induced
M. Furthermore, many sets of genes, including the novel genes
identified to be selectively expressed in DCs, should provide further
understanding of the biological function of DCs in the host defense system.
| |
MATERIALS AND METHODS |
Preparation of cells.
Peripheral blood mononuclear cells (PBMCs) were isolated from venous
blood drawn from normal healthy volunteers at the Tokyo Metropolitan
Red Cross Blood Center (Tokyo, Japan). Briefly, PBMCs were isolated by
centrifugation on a Ficoll-Metrizoate density gradient (d = 1.077 g/mL; Lymphoprep; Nycomed, Oslo, Norway) and suspended in
RPMI 1640 medium containing 7.5% heat-inactivated fetal calf serum
(FCS; GIBCO/Life Technologies, Tokyo, Japan), 100 µg/mL streptomycin,
and 100 U/mL penicillin. The FCS contained 3 pg of LPS per milliliter
as assessed by a Limulus amebocyte lysate. PBMCs were incubated with
anti-CD14 monoclonal antibody (MoAb) coated with microbeads, and Mo
were isolated by passing the PBMCs through a magnetic cell separation
system (MACS; Miltenyi Biotec, Bergisch Gladbach, Germany) with column
type VR. These cell suspensions were then aliquotted into plastic
tissue culture plates and incubated for 30 minutes at 37°C, 5%
CO2 to obtain the highly purified cells. More than 99% of
the cells were judged to be Mo by morphology, by positive staining for
CD14 (LeuM3; Becton Dickinson, San Jose, CA) in a flow cytometric
analysis, and by nonspecific esterase staining.
Phenotyping with MoAbs.
The expression of leukocyte cell surface markers and cytoplasmic
antigens was assessed. The cells were sequentially incubated with
optimal concentrations of biotinylated anti-CD86 (2331; PharMingen, San
Diego, CA) and anti-CD1a MoAbs (HI 149; PharMingen), followed by
fluorescein isothiocyanate (FITC)-labeled streptavidin
and by phycoerythrin (PE)-conjugated goat antimouse IgG,
respectively, or directly stained with FITC-labeled anti-HLA-DR (4C3;
PharMingen), mouse anti-CD80 (MAB104; Coulter, Fullerton, CA), CD83
(HB15a; Coulter), and PE-labeled anti-CD14 (M5E; PharMingen), CD33
(B8.12.2; Immunotech, Marseille Cedex, France) MoAbs. To block
nonspecific FcR-mediated binding of MoAbs, cells were incubated for 60 minutes at 4°C with normal goat serum (Cedarlane Laboratories Ltd,
Hornby, Ontario, Canada) before staining. For all experiments,
irrelevant control MoAbs of the same IgG isotype and second-step
controls were included. Stained cells were fixed with 1%
paraformaldehyde (Sigma, St Louis, MO). For all labeling
experiments, analysis was performed using the EPICS ELITE (Coulter
Electronics, Hialeah, FL).
SAGE protocol.
mRNAs of monocytes, macrophages, and monocyte-derived DCs were purified
from a mixture of total RNA of 8 donors. Monocytes were incubated with
IL-4 (100 U/mL; Ono Pharmaceutical Co, Ltd, Osaka, Japan)
or GM-CSF (500 U/mL; Kirin Brewery Co, Ltd, Tokyo, Japan) in RPMI1640
containing 7.5% FCS in 5% CO2 at 37°C for 7 days.
Total RNA from these cells was isolated by direct lysis in RNAzol B
(TEL-TEST, Inc, Friendswood, TX). Poly(A)+ RNA were isolated using the
FastTrac mRNA purification kit (Invitrogen, Carlsbad, CA) according to
the manufacturer's instructions. SAGE was performed as
described.9-12 SAGE libraries were generated using 2.5 µg
poly(A)+. RNA was converted to complementary DNA (cDNA) with a BRL
synthesis kit (GIBCO BRL) following the manufacturer's protocol, with
the inclusion of primer biotin-5'-T18-3'. The cDNA was
cleaved with the restriction enzyme Nla III, and the
3'-terminal cDNA fragments were bound to streptavidin-coated
magnetic beads (Dynal, Oslo, Norway). After ligation to
oligonucleotides containing recognition sites for BsmF1, the
linkered cDNAs were released from the beads by digestion
with BsmF1. The released tags were ligated to one another,
concatemerized, and cloned into the Sph I site of pZero 1.0 (Invitrogen). Colonies were screened with polymerase chain reaction
(PCR) using M13 forward and M13 reverse primers. PCR
products containing inserts of greater than 400 bp were sequenced with
the TaqFS Dyeterminater kit and analyzed using a 377 ABI automated
sequencer (Perkin-Elmer, Branchburg, NJ). All electropherograms were
reanalyzed by visual inspection to check for ambiguous base and to
correct misreads.
SAGE was performed on mRNA from human Mo, GM-CSF-induced M, and
Mo-derived DCs. Sequence files were analyzed with the SAGE software,10 CGAP SAGEdatabase
(http://www.ncbi.nlm.nih.gov/SAGE/), the NCBI's sequence search tool
(Advanced BLAST search, http://www.ncbi.nlm.nih.gov/BLAST/), and DNAsis
software (Takara, Shiga, Japan). After the elimination of
linker sequences and the repeated ditags, a total of 173,563 tags,
representing 57,560, 57,463, and 58,540 from human Mo, GM-CSF-induced M, and monocyte-derived DC, respectively, were analyzed.
Reverse transcriptase-PCR (RT-PCR).
Total RNAs (200 ng) were prepared using RNAzol B. The RNA was
reverse-transcribed in 50 µL of 10 mmol/L Tris-HCl (pH 8.3), 6.5 mmol/L MgCl2, 50 mmol/L KCl, 10 mmol/L dithiothreitol, 1 mmol/L of each dNTP, 2 µmol/L random hexamer, and 2.4 U/µL of
Moloney murine leukemia virus reverse transcriptase for 1 hour at
42°C. cDNA, corresponding to 40 ng of total RNA, was boiled for 3 minutes and quenched on ice before amplification by PCR. The conditions for PCR were as follows: in a 50 µL reaction, 15 µmol/L of each primer; 125 µmol/L each of dGTP, dATP, dCTP, and dTTP (Toyobo, Osaka,
Japan); 50 mmol/L KCl; 10 mmol/L Tris-HCl, pH 8.3; 1.5 mmol/L
MgCl2; and AmplyTaq (Perkin-Elmer). Primers used were as follows: TARC: sense, 5'-ATGGCCCCACTGAAGATGCT-3', and
antisense, 5'-TGAACACCAACGGTGGAGGT-3'; MCP-4: sense,
5'-ATGACAGCAGCTTTCAACCCC-3', and antisense,
5'-CTCCAAACCAGCAACAAGTCAAT-3'; Thymosin  10: sense, 5'-TGGCAGACAAACCAGACATGG-3', and antisense,
5'-ATTTGGCAGTCCGATTGGG-3'; phosphofructokinase: sense,
5'-TTTCAAGATGCGGTTCGACT-3', and antisense, 5'-AATCCACCGATGATCAGCAG-3'; hepatocyte growth factor
inhibitor type 2: sense, 5'-ATCCACGACTTCTGCCTGGT-3',
and antisense, 5'-CGGCAGCCTCCATAGATGAA-3'; metalloproteinase: sense, 5'-TTTTGCCCGTGGAGCTCAT-3', and
antisense, 5'-TTCCCACGGTAGTGACAGCA-3';
tristetraprolin: sense, 5'-CCCTGATGAATATGCCAGC-3', and
antisense, 5'-GGTTCATTGCCTCCCTTAAA-3'; cathepsin C: sense, 5'-TTTCTCAGCTCCCTGCAGCA-3', and antisense,
5'-CATGCACCCACCCAGTCATT-3'; and CD14: sense,
5'-CGGTCTCAACCTAGAGCCGTTT-3', and antisense, 5'-TGGGCAATGCTCAGTACCTTG-3'. Reaction mixtures
were incubated in a Perkin-Elmer DNA Thermal Cycler for 25 to 30 cycles
(denaturation for 60 seconds at 94°C, annealing for 60 seconds at
58°C, and extension for 120 seconds at 72°C).
Statistical analysis.
Statistical significance between samples was calculated as described
previously.13
| |
RESULTS |
Surface phenotype of normal human blood Mo-derived DCs.
To identify genes specifically expressed in DCs, SAGE libraries were
generated from highly purified resting human Mo-derived DCs
differentiated by GM-CSF + IL-4 + TNF-. Peripheral blood CD14+ Mo were cultured with GM-CSF + IL-4 + TNF- for 5 days. Under these culture conditions, the cells differentiated into
nonadherent CD14, CD1a+,
CD80low/, CD86low/,
HLA-DR+, CD33+, and CD83
cells with the dendritic morphology of immature DCs
(Fig 1).
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| Fig 1.
Surface phenotype of normal human blood Mo-derived DCs.
DCs were cultured in RPMI-1640 medium plus 7.5% FCS in the presence of
GM-CSF (500 U/mL), IL-4 (100 U/mL), and TNF- (50 U/mL) for 5 days.
After culture, the cells were washed and then stained with various
antibodies as described in Materials and Methods. The data are shown as
histograms depicting the number of cells exhibiting various
fluorescence intensities. The dotted lines represent staining with
specific antibodies and the solid lines represent the isotype-matched
control. Results are representative of 3 independent experiments.
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SAGE tag abundance expression in Mo-derived Dcs.
A total of 58,540 tags sequences from the DC library
allowed identification of more than 17,000 different genes, with more than 5,000 genes appearing more than two times. Next, the expressed genes were searched for through the GenBank database to identify individual genes. Table 1 shows the top 50 transcripts in Mo-derived DCs. The most expressed genes in human DCs
were identified as HLA DR invariant chain (expression frequency,
1.67%) and ferritin L-chain (1.44%) and HLA DR chain (1.17%).
Overall, the genes expressed abundantly in the DC library consist of
products associated with major histocompatibility complex
(MHC) class I and class II, protein synthesis, and the
cytoskeleton. These data agree with previous data showing high
expression of MHC class I and class II genes in DCs, and expression of
genes encoding cytoskeleton-associated molecules may be necessary for
forming dendrites needed to interact with T cells and B cells.
Comparison of expression patterns in Mo-derived DCs.
Comparison of the expressed genes between Mo14 and DCs
showed that the expression levels of most of the transcripts
(>20,000) in these cells were similar
(Fig 2). However, the expression profiles also showed 313 transcripts in Mo that were different from those in DCs
(P < .01). Expression levels of 181 of 313 genes were
decreased in DCs as compared with those in Mo. Conversely, 132 transcripts were expressed at higher levels in the DCs than in Mo.
Table 2 shows the top 50 that were
increased transcripts in DCs compared with Mo. In addition, the gene
expression compared between DCs and GM-M14 shows a
similar pattern (Table 2). The transcripts increased in DCs mainly
consist of genes encoding proteins associated with cell structure such
as gelsolin and vinculin, lipid metabolism such as lysosomal acid
lipase and apolipoprotein C-1, and chemokines such as TARC, MDC, and
MCP-4. The expression of gelsolin, lysosomal acid lipase, MDC, fatty
acid binding protein homologue, acid phosphatase type 5, GA733-1, CD9,
HSP27, etc, was increased in M as well as in DCs. On the other hand,
TARC, hepatocyte growth factor activator inhibitor type-2 (HAI-2),
platelet-type phosphofructokinase, factor XIII,15
CD23,16 cathepsin C, MCP-4, and metalloproteinase were
highly specific for DCs (Fig 3).
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| Fig 2.
Comparison of gene expression frequency in Mo and
Mo-derived DCs. A semilogarithmic plot shows 105 tags that were
decreased more than 10-fold in DCs compared with Mo, whereas 109 tags
were increased more than 10-fold in DCs compared with Mo. The relative
expression of each transcript was determined by dividing the number of
tags observed in Mo or DCs, as indicated. To avoid division by 0, we
used a tag value of 1 for any tag that was not detectable in 1 sample.
These ratios are plotted on the abscissa. The number of genes
displaying each ratio is plotted on the ordinate.
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| Fig 3.
RT-PCR analysis of genes expressed differently in Mo,
GM-CSF-induced M, and DCs. RT-PCR was performed on total RNA
isolated from (1) human Mo, (2) GM-CSF-induced M, and (3)
Mo-derived DCs as described in Materials and Methods. (A) through (D)
indicate different donors.
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Table 3 shows the top 50 transcripts
decreased in DCs. The most decreased mRNAs were identified complement
proteins; ficolin and properdin; DNA-binding proteins; GOS3, GOS2, and
c-fos; surface protein; and CD14. The decreased transcripts in DCs
showed a similar tendency in GM-M. Moreover, transcripts decreased
more than 10-fold compared with GM-M were MRP-14, macrophage
inhibitory protein-1 (MIP-1), CD14, 1
antitrypsin, HLA-B, and transletolase. The reduction of CD14 in DCs was
also confirmed by a flow cytometric analysis (Fig 1).
RT-PCR of genes represented in the SAGE analysis.
Although our data represent the average gene expression on cells
obtained from 8 donors, there could be differences in gene expression
between individual donor-derived cells. To address this question, we
arbitrarily selected 9 differently expressed genes and evaluated them
in 4 donor-derived samples by RT-PCR (Fig 3). The expression of each
transcript was compared with SAGE data. Thymosin 10 was expressed
in all cell types (Mo, 214; GM-M, 246; and DCs, 273);
TARC was highly expressed in DCs (Mo, 0; GM-M, 1; and DCs, 122);
MCP-4 was highly expressed in DCs (Mo, 0; GM-M, 0; and DCs, 18);
cathepsin-C was highly expressed in DCs (Mo, 0; GM-M, 1; and DCs,
18); phosphofructokinase was highly expressed in DCs (Mo, 0; GM-M,
0; and DCs, 31); HAI-2 was highly expressed in DCs (Mo, 0; GM-M, 4;
and DCs, 40); metalloproteinase was highly expressed in DCs (Mo, 0;
GM-M, 0; and DCs, 15); tristetraproline was highly expressed in Mo
(Mo, 44; GM-M, 0; and DCs, 1); and CD14 was highly expressed in Mo
(Mo, 84; GM-M, 10; and DCs, 0). These results confirm our SAGE data
for Mo, GM-M, and DCs and establish the general expression profile
of the identified genes.
| |
DISCUSSION |
It is an important to clarify the origin and nature of DCs to exploit
them as therapeutics and vaccines. The heterogeneity of
DCs, which have various functions, may depend on differences in
specific gene expression induced by growth factors, such as IL-4,
TNF-, transforming growth factor- (TGF-), and
GM-CSF. Thus, to investigate the function of gene
regulation in DCs, we performed SAGE in human blood Mo-derived DCs
induced by GM-CSF, IL-4, and TNF-.
A technology that yields identification of differently expressed genes
can provide an important tool for the understanding of cell biology.
Several methods, such as Northern blotting, RT-PCR, differential
display, and subtraction, are useful for such studies. However, these
technologies can analyze only a limited numbers of genes, and the
quantitative analysis of the transcription of individual genes is
difficult. SAGE allows both quantitative and simultaneous analysis of
large numbers of transcripts. We investigated a total of 173,562 tags
derived from 57,559, 57,463, and 58,540 tags from Mo, GM-M, and DCs,
respectively, which allowed for the identification of 36,605 different
gene transcripts. Sequences from the DC library
represented more than 17,000 different genes, with more than 5,000 genes appearing more than 2 times.
We observed many genes expressed in DCs that have not been identified
before this analysis. One of these, HAI-2, which is highly specific for
DCs and is a Kunitz-type serine protease inhibitor, has been found to
be an inhibitor of hepatocyte growth factor activator (HGF) responsible
for proteolytic activation of HGF.17,18 Another group has
identified the same gene (kop, from pancreatic cancer), which may
participate in tumor cell invasion and metastasis. Therefore, HAI-2 may
be involved in the regulation of proteolytic activation of HGF in
injured tissue or the migration of cells. Moreover, another differently
expressed gene in DCs, a metalloproteinase that possesses elastolytic
activity,19 is also thought to be a candidate molecule for
the cause of diseases characterized by damage to the extracellular
matrix or cell migration. It is predicted that alteration of expression
of many cytoskeleton proteins is involved in the change of cell
migration. In addition to the top 50 differently expressed genes in
DCs, the expression of genes encoding proteins associated with cell
structure such as thymosin -4 (tag number; Mo, 223; and DCs, 486),
-actin (Mo, 53; and DCs, 108), -actinin (Mo, 1; and DCs, 13),
vimentin (Mo, 82; and DCs, 187), and profilin (Mo, 83; and DCs, 167)
was also increased in DCs as compared with Mo. Taken together, all of
these data suggest that differentiation from Mo into DCs is accompanied
by a significant change in the expression of genes related to cell structure and motility.
Interestingly, increased expression of the genes encoding chemokines,
such as TARC, MDC, and MCP-4, that selectively chemoattract CCR4- and
CCR3-positive Th2-type lymphocytes,20,21 were observed in
monocyte-derived DCs (Table 2 and Fig 3). In contrast, expression of
the genes encoding chemokines that selectively chemoattract CCR5- and
CXCR3-positive Th1-type lymphocytes, such as IP-10, Mig, and MIP-1,
was not observed in tags of the tested DC library (data not shown).
These results suggests that DCs tested in this study may chemoattract
Th2 cells selectively. Thus, the result was unexpected, because several
groups have demonstrated that activated or mature DCs promote Th1
differentiation through IL-12 production.22,23 A recent
study showed that immature DCs may promote Th2 responses.24
Moreover, it has been reported that Th2 polarity in the resting mucosal
immune system may be an inherent property of the resident DC
population.25 Thus, we presume that Mo-derived DCs might be
critical for polarization or amplification of Th2 cells and play an
important role for Th2-dominated immune diseases such as
asthma26,27 and atopic dermatitis.28,29
In conclusion, identification of the genes selectively expressed in
human Mo-derived DCs should provide useful information for defining the
development and function of DCs. Furthermore, many sets
of genes, including the novel genes identified to be selectively
expressed in DCs, should provide further understanding of the
biological function of DCs in the host defense system and may also be
useful for diagnosing or monitoring human diseases in which DCs may
play a role.
| |
ACKNOWLEDGMENT |
The authors are very grateful to Drs V. Velculescu, L. Zhang, W. Zhou,
B. Vogelstein, and K. Kinzler for their help in SAGE analysis and also
to Dr H. Young and Dr C. Vestergaard for reviewing this manuscript.
| |
FOOTNOTES |
Submitted February 11, 1999; accepted March 22, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Kouji Matsushima, MD, PhD, Department of
Molecular Preventive Medicine, School of Medicine, University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; e-mail:
koujim{at}m.u-tokyo.ac.jp.
| |
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ABSTRACT
INTRODUCTION