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Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1432-1441
Expression Profile of Active Genes in Granulocytes
By
Koichi Itoh,
Kousaku Okubo,
Hiroyasu Utiyama,
Tetsuo Hirano,
Junji Yoshii, and
Kenichi Matsubara
From the Institute for Molecular and Cellular Biology, Osaka
University, Yamada-oka, Suita, Osaka, Japan; the Life Science Group,
Faculty of Integrated Arts and Sciences, Hiroshima University,
Kagamiyama, Higashihiroshima, Hiroshima, Japan; and Hitachi Software
Engineering, Co, Ltd, Onoe-chou, Naka-ku, Yokohama, Japan.
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ABSTRACT |
A number of genes active in granulocytes have been intensively
studied as to the function of their products and their expression controls. However, the intensities and relative order of these gene
activities have not been studied. This report describes an expression
profile of 748 different species of active genes in human peripheral
granulocytes obtained by analyzing a 3 -directed cDNA library
that faithfully represents the mRNA population in the source cells. A
significant fraction (20.3% of the total) of the expressed genes in
granulocytes consisted of nuclear proteins such as DNA binding
proteins, of secretory proteins such as cytokines, and of membrane
proteins such as major histocompatibility complex (MHC)
proteins and receptors. By comparing this expression profile with 11 profiles similarly obtained with unrelated human cells/tissues, we
discovered 10 novel genes that are likely to act specifically in
granulocytes. Comparison of this expression profile with that obtained
with granulocytoids widely used as a granulocyte model by inducing a
cultured promyelocytic leukemia cell line HL60 showed similarities and
dissimilarities of gene expressions.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
GRANULOCYTES ARE short-lived cells for
body defense, with a half-life of 6 to 7 hours in blood. Because of
this short life span, their protein synthetic apparatus is poorly
developed,1,2 but they maintain active genes that are
responsible for their unique activities. These genes have been the
focus of intensive study.
We have initiated a systematic survey of active genes, as well as the
relative abundance of mRNA expression, in granulocytes using an
expression profiling method that is based on quantitative analysis of
mRNA populations.3 This is performed by using
3-directed cDNA libraries that faithfully represent the mRNA
population and by obtaining short base sequences just upstream of
polyA, called gene signatures (GSs), by single-pass sequencing of
randomly selected clones from such libraries.3-5 Active
genes are identified by sequences and the gene activities are
identified by their recurrences. The resulting list showing the
expressed gene species and the abundance of their transcript is called
an expression profile, which illuminates the gene-product-based
cellular phenotype.
In the profile are represented several known genes as well as novel
genes. These genes can be categorized as those that are commonly
expressed in different types of cells (candidate genes for housekeeping
functions) and those that are expressed uniquely in granulocytes
(candidate genes for granulocyte-specific functions). We used 11 expression profiles obtained with different human cells/tissues for the
gene categorization and discovered some genes that are likely to be
granulocyte-specific, even though we do not yet know their functions.
A promyelocyte cell line, HL60,6 is converted into
granulocytoid cells by treatment with dimethylsulfoxide (DMSO). The cells stopped proliferating, the nucleus became pyknotic and
polymorphic, and the cells expressed several genes unique to
granulocytes. Thus, because they are morphologically and functionally
similar to granulocytes, the cells are referred to as granulocytoids
and are widely used as a model system for studies of
granulocytes.7-10 We monitored the expression
profile of these cells. Comparison of this profile with that of the
peripheral granulocytes showed advantages and disadvantages in using
the granulocytoids as a model system.
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MATERIALS AND METHODS |
Preparation of human granulocytes.
Freshly obtained venous blood was diluted with the same volume of
phosphate-buffered saline (PBS), and the suspension was centrifuged on
a ficoll step gradient (upper density, 1.077; lower density, 1.119) for
20 minutes at 3,000g.11,12 Granulocytes collected
from the interface were washed twice with PBS and resuspended in the
same buffer. The purity of the preparation was examined under a
microscope upon Giemsa staining. At least 99% of total cells were
mature granulocytes.
Induction of granulocytoid cells.
HL60 cells (Japanese Cancer Research Resource Bank, Osaka,
Japan) were grown in RPMI 1640 medium (Nissui, Tokyo, Japan)
supplemented with 10% (vol/vol) bovine fetal serum (Hyclone,
Logan, UT) and harvested in the logarithmic phase
(106 cells/mL). Granulocytoid cells were prepared by
seeding HL60 in a plate at a concentration of 2 × 105
cells/mL and incubating in the presence of 1.3% (vol/vol) DMSO (Sigma, St Louis, MO) for 72 hours.
cDNA library construction and sequencing.
RNAs were prepared from the cytoplasmic fraction of DMSO-induced HL60
cells as described3 and from the total cell
lysate13 of granulocytes. Purification of polyA RNA was not
attempted, because of the presence of RNase. Construction of the
3-directed cDNA libraries and transformation into
Escherichia coli were performed by synthesizing cDNA using
pUC19-based vector primer, digesting with dam-sensitive four-base
cutter Mbo I, followed by circularization and transformation
into E coli.4 The transformant colonies were
randomly selected and cultured in 96-well plates, and the inserted
cDNAs were amplified with flanking primers and subjected to cycle
sequencing.
Data analysis.
The polyA tail was removed from the sequencing data after checking the
electropherograms, leaving 3 As as a marker. From the resulting
sequence data, those having inserts shorter than 20 bp or those having
more than 5 ambiguous bases (N) within the initial 100 bases were
discarded. The sequences of the remaining clones were truncated where
the N content exceeded 5%, and the final N was replaced by an X to
mark the point of truncation. The resulting sequences are referred to
as GSs.
The GSs were compared using the FastA program.14 Identical
signatures were lumped together, and a representative sequence that had
the lowest content of ambiguous bases was selected to represent the
group and deposited in the DDBJ, wherein the locus name corresponds to
the GS number (such as HUMGS01234 to GS01234). All the representative
GSs were searched against GenBank (Re95) using the FastA
program,14 and those that had greater than 90% similarity
to the 3 end of the mRNA entries or to the reported terminal
exon of genes were regarded as representing the corresponding genes.
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RESULTS |
Expression profiles of active genes in granulocytes.
From the 3-directed cDNA library constructed from human
peripheral granulocytes, we randomly selected 1,142 independent clones and sequenced them. Among the resulting short sequences called GSs,
representing just upstream of the polyA, sequences that were considered
essentially identical were lumped together to represent the same gene
species. After this treatment, 748 independent GS species resulted.
Among them, 216 (28.9%) represented by 493 clones were identified in
GenBank (Re95), and the remaining 532 (71.1%), represented by 649 clones, were from novel genes.
Table 1A shows an expression
profile of active genes as represented by their GSs and their
activities with their relative abundance. We listed here only those 64 GSs that appeared 3 times or more in descending order of appearance.
Those genes that appeared twice or less can be seen in www bodymapper
server (http://www.imcb.osaka-u.ac.jp/bodymap). We believe that this is
the first publication describing relative activities of genes in
granulocytes that are expressed abundantly. The profile reflects
several unique features of the granulocytes physiology. First, it
includes several genes that have been well known in peripheral
neutrophils, such as genes for  2-microglobulin,15 granulocyte colony-stimulating factor receptor,16-18 major
histocompatibility complex (MHC) class I, and so on. Genes
whose activity has been detected in granulocytes15-36 are
marked with asterisks. High activities of genes for spermidine/spermine
N1-acetyltransferase, pre-B-cell enhancing factor (PBEF), and B94
protein are also noted. The purity of the source material guarantees
that this result reflects the relative activities of those genes.
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Table 1.
Expression Profile of Active Genes in Human Peripheral
Granulocytes (A) and Granulocytoids by Inducing HL60 With DMSO (B)
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We categorized the 493 known genes active in the granulocytes into
subgroups according to their function and subcellular localization. The
results are collectively shown in
Table
2. The most prominent feature of granulocytes is the high activity with
genes for cell surface membrane components. Thirty GS species
represented by 114 clones (Table 2J), amounting to 10% of the mRNA
population, were of this category. Genes for nuclear DNA binding
protein, components for secretory protein, and components for signal
transduction were also noticeably active. Genes for energy
production, lysosomal proteins, protein synthesis machinery, and
cytoskeleton are not so active in the granulocytes, as had been
expected.
Comparison of gene activities in granulocytes and DMSO-induced
granulocytoids.
An expression profile of the granulocytoid cells is represented in
Table 1B (column GR). In the same table are collectively displayed the
relevant gene activities with HL60 cells (HL) and the monocytoids
derived from HL60 by tetradecanoylphorbol-13 acetate (TPA)10 treatment (MO). Comparison of Table 1B with Table
1A or column PM versus GR in Table 1A with column GR versus PM in Table
1B shows that about 50% (24/48) of the abundantly expressed genes in
the DMSO-induced HL60 are also present in peripheral granulocytes,
although the abundances differ. Scarcity of highly abundant transcripts
is characteristic of the mRNA population in granulocytoid cells.
Generally, genes for cytoskeleton and protein synthesis machinery are
moderately active, unlike genes for cell surface membrane components in
granulocytoid cells. Further discussions will be presented in the
Discussion.
Identification of granulocyte-specific genes.
We have prepared expression profiles of active genes in 11 other human
cells/tissues.3,10,37 Genes listed in Table 1A and B were
extracted from each of these profiles, and their activities (abundance
of the transcripts among 1,000 mRNA molecules) were compiled. The
resulting Table 1A, although incomplete, allows us to categorize genes
into those whose expression is peripheral granulocyte-specific, limited
to certain types of cells, or ubiquitous. When the genes have been
detected in 6 libraries or more, we categorized them as ubiquitous
(solid area in column "lib"). Genes known to perform
house-keeping functions, such as ubiquitin or ribosomal proteins, are
seen in this category. A gene expressed only in granulocytes or in
granulocytes and/or granulocytoid cells may be categorized as
unique to this type of cell (open area). The rest were categorized as
common or intermediate (hatched area). We categorized 22 GSs as unique,
among which 12 were identified in GenBank and 10 represent novel genes.
Among the 12 known genes are granulocyte colony-stimulating factor
receptor, interleukin-8 (IL-8), leukocyte common antigen T200 (CD45),
and ICAM-3, which have been known to act mainly in granulocytes. No
data have been reported so far as to the cell type specificity of the
remaining 8 genes. Thus, at least one third of the genes in the unique
category were indeed those that represent specific functions of the
granulocytes. We argue that we can extrapolate this finding to the
novel genes.
dbEST and the granulocyte GS.
As a result of a rapid expansion in the collection of expressed
sequence tags (ESTs), more than 400,000 fragmentary human cDNA
sequences from more than 20 tissues have been collected in dbEST. This
database can be readily compared with the expression profiles as
described here, because the quality of the source cells for this
library construction has not been biased and because the cDNA libraries
that have been subjected to normalizing protocol do not reflect the
composition of the mRNA population in the original source
cells/tissues. Nevertheless, they can provide some information as to
what RNA species are present in tissues so far examined. We queried the
22 GS sequences that were categorized as unique with dbEST. The
results, shown in Table 3, demonstrate that
5 of them, GS08339 (IL-8), GS05242, GS01594 (leukocyte common antigen T200), GS08389 (E4BP4 gene), and GS08424 have not been registered in
dbEST. Considering that no granulocytes or related tissues were used
for the EST collection, it is not surprising that these sequences
failed to appear in dbEST. From an opposite point of view, the absence
in dbEST strengthens the idea that such genes are unique to the
granulocytes. Five GSs, GS08362 (granulocyte colony-stimulating factor
receptor), GS08347, GS08438 (Nramp), GS08336 (secretory granule
proteoglycan peptide), and GS08375 (MAD-3) matched ESTs from fetal
liver spleen, placenta, lung, and other tissues. This observation shows
the limit of the application of dbEST for the categorization under
discussion: it may simply show that tissues used in the dbEST data
construction contained some granulocytes. As with novel genes, one GS
(GS08347) is highly likely to represent a gene that is unique to
granulocytes. The other 9 genes were subjected to further examination,
because they were found recurrently in tissues not related to
granulocytes in the dbEST.
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DISCUSSION |
The cell physiology reflected in the expression profile of
active genes.
Granulocytes are a major player in the defense of the body against
foreign materials. About 90% to 95% of granulocytes are neutrophils,
with the remainder being eosinophils and basophils in circulating human
blood. Hence, peripheral granulocytes represent the activities of
neutrophils.1 The cytoplasm of these cells has highly
developed cytomatrixes, as well as granules that contain microbicidal
proteins and digestive enzymes. The plasma membranes carry a number of
receptors and other structures needed for recognition and disposal of
invading pathogens.2
Although gene activities are not necessarily reflected by the abundance
of mRNA, other methods being not available (except for quantitizing
two-dimensionally separated protein bands), gene expression
profiling3 leads to the best approximation. Table 1A shows
several genes well studied in conjunction with the functions in
granulocytes. The quantitative ratios should help us understand the
regulatory systems acting in the granulocytes. An abundant expression
of genes for cell surface membrane proteins drew our attention; eg,
genes for 2-microglobulin, MHC class I HLA-Cw, and HLA-E heavy
chain, which are components of cell surface receptors. That a lot of
genes for cell surface membrane proteins are active in granulocytes
supports the notion that granulocyte responses can be evoked by a
variety of stimuli caused by particulate and soluble materials. On the
other hand, most of the genes for cytoskeleton were not so active,
except those for thymosin 4 and -actin, in accord with the notion
that these cells do not maintain a rigid shape.
The list has shown several genes not known to be active in
granulocytes. This study points out the importance of elucidating the
role of gene products in granulocytes. B94 protein and B4-2 protein are
good examples. Expected changes in the expression of genes in
association with inflammation or changes in adhesive properties during
chemotaxis and phagocytosis remain to be examined. Fibronectins,
2-integrins, and the L-selectins, which are notably associated with
adhesiveness as mediators,2 were not detected in our
expression profile. Actins, which play important roles in production of
pseudopodium for locomotion, were not expressed strongly. Activation of
these genes is yet another feature of the activation of granulocytes
worth investigating. Genes for chemotactic factor receptors were
moderately expressed, including tumor necrosis factor receptor,
N-formylpeptide receptor, C5a anaphylatoxin receptor, and IL-8
receptor. On the other hand, expression of receptors for C3b and C3bi
were not detected, in line with the fact that our granulocytes were in
a resting stage.38 Here again, examination of the profile
in induced cells, including the time course of activation and their
relative order of activities, is of utmost interest.
Genes for secretory proteins, such as cytokines, are not particularly
active in circulating granulocytes and, indeed, only 2 genes, for
pre-B-cell colony-enhancing factor and IL-8, were detected. Thus, the
relative activities of these important granulocyte-specific genes in
resting cells have been determined. As with secretable bactericidal
components, there were cathepsin S, neutrophil oxidase factor
(NCF2)/p67-phox, proteasome subunit p40, and defensin, in addition to
lysosomal proteins. Thus, these proteins are constitutively produced at
a level of 4.0% or more of total protein synthesis. Bactericidal/permeability-increasing protein (BPI) was found in granulocytoid cells, but not in the peripheral granulocytes, probably because its expression level is just at the border of the level of
detection.
Whereas active expressions of genes for cell surface membrane proteins,
including receptors for chemotactic factors as well as genes for
bactericidal proteins such as lysosomes, are characteristic to our
granulocytes, so is poor expression of components for protein synthesis
machinery, as it is for cells in the resting stage.
Among the mRNAs in granulocytes identified in GenBank (Table 1A) are
genes for granulocyte colony-stimulating factor receptor, tumor
necrosis factor receptor, and T200. These gene products are related to
neutrophilic granulopoiesis and their maturation. Thus, these findings
strongly suggest that granulocytes in circulating blood wait for
stimuli exposing granulopoietic receptors. The list also included IL-8,
a neutrophilic chemoattractant and activator. In contrast to IL-8
receptor (Table 2J), IL-8 is highly and specifically expressed. This
mRNA has been known to be induced in neutrophils in response to
granulocyte/macrophage colony-stimulating factor.31,39 Although granulocyte colony-stimulating factor regulates the expression of IL-8 receptor,40 whether granulocyte colony-stimulating
factor can induce the expression of IL-8 is not clear. Our results
indicate that granulocyte colony-stimulating factor induces the
expression of IL-8 mRNA.
The uniquely active genes in granulocytes.
Among the 22 genes categorized as unique in Table 1A, 10 were novel
genes. It is of utmost importance to characterize these genes, although
such categorization can be performed only with abundantly expressed
genes, and yet some misleading categorizations are unavoidable due to
the limited number of GS collections.
Comparison of expression profiles between granulocytes and
granulocytoid cells induced from HL60.
2-microglobulin and HLA-E heavy chain were commonly expressed in
granulocytes and granulocytoid cells. Proteins in lysosomes, BPI, and
leukocyte adhesion protein (Mac-1), which are known to be expressed in
neutrophils, were also expressed in granulocytoid cells. In total, 20%
or more of the mRNAs are commonly expressed in both types of cells
(data not shown).
However, their relative proportions in granulocytoids differ from those
in granulocytes. In general terms, expression profiles of genes in
granulocytes and granulocytoid cells differ from each other
qualitatively and quantitatively. In Table 1A, 24 gene species
represented by 74 clones were commonly expressed in granulocytes and
granulocytoid cells. These observations demonstrate the capacity and
limitations of this model system.
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FOOTNOTES |
Submitted December 29, 1997;
accepted April 22, 1998.
Address reprint requests to Kenichi Matsubara, PhD, Nara Institute of
Science and Technology 8916-5, Takayama, Ikoma, Nara 630-01, Japan;
e-mail: kenichi{at}bs.asist-nara.ac.jp.
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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Taub DD,
Xu L,
Michiel D,
Sprenger H,
Oppenheim JJ,
Kelvin DJ:
Granulocyte-colony stimulating factor and lipopolysaccharide regulate the expression of interleukin 8 receptors on polymorphonuclear leukocytes.
J Biol Chem
270:28188,
1995[Abstract/Free Full Text]
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Abstract
Introduction
Abstract