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*
Departments of Microbiology/Immunology and Medicine and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, and Walther Cancer Institute, Indianapolis, IN 46208; and Departments of
Molecular Virology and Host Defense, Collegeville, PA 19426 and
Molecular Immunology, SmithKline Beecham Pharmaceuticals and King of Prussia, PA 19406
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, and TNF-
. Taken together, our findings suggest that
MIP-3ß is expressed in the bone marrow environment after induction
with certain inflammatory cytokines and LPS, and may play a role in
trafficking of macrophage progenitors in and out of the bone marrow in
inflammatory conditions. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chemokines are small peptide molecules of 8 to 12 kDa and have a number of functions such as leukocyte trafficking, angiogenesis, regulation of hemopoiesis, suppression of HIV infection, and antitumor effect (4). Stromal cell-derived factor-1 (SDF-1) is the first chemokine shown to have the capacity to attract CD34+ cells and HPC (1). SDF-1, a CXC chemokine, has chemotactic activity for CFU granulocyte macrophage (CFU-GM), burst-forming unit erythrocyte (BFU-E), and CFU granulocyte, erythrocyte, macrophage, and megakaryocyte (GEMM) (1, 3). Mice deficient in SDF-1 had defects in BM hemopoiesis (5). The CC chemokine MIP-3ß/EBI1-ligand chemokine/CKß-11 (hereafter termed MIP-3ß) has recently been described as a ligand for the EBI1/BLR2/CCR7 receptor (6). Its mRNA is detected in thymus and secondary lymphoid organs (6, 7). MIP-3ß is distantly related to other CC chemokines, forming a separate subfamily of this group (8). The chromosomal location of MIP-3ß is different from other CC chemokines in that the gene for MIP-3ß is localized on chromosome 9, while most other CC chemokine genes are found on chromosome 17. EBI1/BLR2/CCR7, the only identified receptor for MIP-3ß, had been initially identified on EBV-transformed B cell lines and also on T cell lines (9, 10). MIP-3ß attracts thymocytes (25) and T and B lymphocytes, but not monocytes or granulocytes (11).
In this study, we report that MIP-3ß is another chemoattractant for BM and cord blood (CB) CD34+ cells and HPC. However, unlike SDF-1, MIP-3ß shows relatively specific chemotactic activity for HPC restricted to macrophage differentiation. We also observed that mRNA expression of this CC chemokine is inducible in BM stromal cells by inflammatory cytokines and LPS. MIP-3ß is the first reported chemokine with relatively restricted chemotactic activity for subtypes of BM and CB HPC.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BM and CB CD34+ cells were purified as previously described (3). The purity of isolated BM CD34+ cells was 93 to 98%, and that of CB CD34+ cells was 85 to 95%. For short-term storage, CD34+ cells were maintained in X-VIVO 20 medium (BioWhittaker, Walkersville, MD) supplemented with 20% FBS (HyClone, Logan, UT), and were used within 20 h after isolation.
BM stromal cells were derived from low density BM mononuclear cells. Low density BM cells were incubated in X-VIVO 20 medium (BioWhittaker) supplemented with 20% FBS. After 2 to 3 wk, monolayers of BM stromal cells, fibroblast-like cells, were used for RT-PCR analysis of MIP-3ß mRNA expression.
Chemokines and Abs
MIP-3ß was expressed in Chinese hamster ovary (CHO) cells (11). Expression, purification, N-terminal analysis, and matrix-assisted laser desorption ionized (MALDI) mass spectrometry for MIP-3ß was conducted, as previously described (11, 12). The MIP-3ß expressed from CHO cells used in this study lacked 5' carboxyl-terminal amino acids from the expected 77-amino-acid protein. Full-length MIP-3ß was also expressed in a baculovirus system. Both truncated and full-length MIP-3ß were equally active in inducing calcium mobilization in RBL (rat basophilic leukemia) cells that were transfected with CCR7 (EC50 range: 1–4 nM). We consistently used the mammalian cell (CHO cells)-derived MIP-3ß in this study.
mAb to human CD34 (clone anti-HPCA-2), conjugated with fluorescent phycoerythrin (PE), was obtained from Becton Dickinson (San Jose, CA). SDF-1 was a kind gift from Dr. Ian Clark-Lewis (University of British Columbia, Vancouver, Canada).
Chemotaxis assay
Chemotaxis and chemokinesis were assayed by a two-chamber cell migration system (3). Chambers were incubated at 37°C, 5% CO2 for 4 to 5 h. Cells completely migrating into the lower chamber were counted using a FACScan (Becton Dickinson, San Jose, CA), with appropriate gating, for 20 s at a high flow rate. For counting only CD34+ cells, migrated cells in staining buffer (PBS containing 1% BSA and 0.01% NaN3) were stained with PE-conjugated anti-CD34 mAb. Isotype-matched mAbs were used to identify negative cell populations. Those cells brighter than isotype-matched Ab-stained cells were counted for 30 s at a high flow rate by FACScan as positive cells.
Colony-forming cell assays for HPC
Methylcellulose colony assay of input or migrated CD34+ cells in response to chemoattractants was performed as described previously (3). BFU-E colonies were scored from plates containing recombinant human (rhu) IL-3, rhuGM-CSF, and EPO, and CFU-GM and CFU-GEMM colonies were scored from plates containing rhu IL-3, GM-CSF, EPO, and steel factor (SLF). rhuEPO was purchased from Amgen (Thousand Oaks, CA) and rhu GM-CSF, IL-3, and SLF were kind gifts of Immunex (Seattle, WA).
For some experiments (Fig. 2
), rhuM-CSF (final concentration of 1000
U/ml) and rhuG-CSF (100 U/ml), gifts respectively of Chiron
(Emeryville, CA) and Immunex, were added to the culture systems in
addition to the cytokines described above. For agarose colony assay,
washed migrated cells were plated in 35-mm plastic tissue culture
dishes (Costar, Cambridge, MA) containing 100 U/ml rhuG-CSF, or 1000
U/ml rhuM-CSF in 0.4% agarose (low melting temperature seaplaque
agarose; FMC, Rockland, ME) culture medium containing 10% FBS (13).
All results from HPC colony assays were reproduced 3 to 10 times.
Cultures were incubated for 14 days at 37°C in a 100% humidified
atmosphere of 5% CO2 at lowered (5%) O2. For
general identification of colony types in granulomonocytic lineages,
colonies grown in methylcellulose media were transferred to glass
plates and stained with Wright-Giemsa staining (Leukostat; Fisher
Scientific, Pittsburgh, PA). For specific identification of macrophage
colonies, the transferred cells on glass plates were stained by
-naphthyl acetate esterase and naphthol
AS-D-chloroacetate esterase staining kits (Sigma, St.
Louis, MO).
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Confluent BM stromal cells grown in 10-cm culture dishes were
treated with LPS (10 µg/ml; Sigma), rhuIFN- (500 U/ml; R&D
Systems, Minneapolis, MN), LPS plus IFN-, rhuTNF- (50 ng/ml; R&D
Systems), G-CSF (50 ng/ml), or SLF (50 ng/ml) for 14 h at 37°C
and 5% CO2. Total RNAs were isolated from the treated
cells with Trizol solution (Life Technologies, Grand Island, NY),
according to manufacturer’s instructions. Single-strand cDNA was made
from the total RNA with SuperScript Preamplification System for First
Strand Synthesis (Life Technologies). Primers used to detect MIP-3ß
mRNA were 5'-ATG GCC CTG CTA CTG GCC CTC AGC CTG-3' for a forward
primer, and 5'-TTA ACT GCT GCG GCG CTT CAT CTT GGC-3' for a reverse
primer, which give PCR products of about 300 bp. PCR reactions were
performed for 40 cycles (94°C, 1 min; 60°C, 1 min; 72°C, 1 min).
To verify that the PCR product indeed coded for MIP-3ß, the PCR
products were gel purified, and DNA sequence was determined by
automated fluorescent dideoxy sequencing. Northern blot analysis of
MIP-3ß expression was performed as previously described (14). For
detection of CCR7 mRNA expression, two primers, 5'-GTC ATC ATC CGC ACC
CTG CT-3' (forward primer) and 5'-GTC TCG GCC TCC ACA CTC ATG-3'
(reverse primer), were used. PCR reactions were performed in the
presence of 0.1 µl of [32P]dCTP (Amersham, Arlington
Heights, IL; 800 mCi/mM/reaction) for 30 cycles (94°C, 1 min; 58°C,
1 min; 72°C, 1 min). The PCR products were resolved on a 5%
nondenaturing polyacrylamide gel. After drying, the filters were
analyzed by Molecular Imager (Bio-Rad, Hercules, CA), and exposed on
x-ray films.
Statistic analysis
Student’s t test was used to analyze data for significance. In each experiment, three plates per point were scored per colony assay. p values less than 0.05 were regarded as significant differences.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We examined a number of new CC and CXC chemokines identified from
the EST data base of Human Genome Sciences for their chemotactic
activities on CD34+ cells. Some of them, now known, were
CKß-1/HCC-1 (15), Exodus-1/CKß-4/MIP-3/liver and
activation-dependent chemokine (LARC) (7, 14, 16, 17),
CKß-6/MPIF-2/Eotaxin-2 (18, 19), CKß-7/MIP-4 (20), CKß-8/MPIF-1
(18), CKß-10/MCP-4 (21), MIP-3ß/EBI1-ligand chemokine/CKß-11 (6, 7), and CKß-12/IL-10-inducible chemokine (GenBank accession numbers:
U91746 and AB007454). MIP-3ß was the only chemokine that had
significant chemotactic activity for CD34+ cells (data not
shown). We examined chemotactic activity of MIP-3ß for BM
CD34+ cells (Fig. 1A). It was observed that BM
CD34+ cells were attracted to MIP-3ß in the lower chamber
of the chemotaxis assay system in a dose-dependent fashion. To exclude
the possibility that migrated cells were not CD34+, but
were contaminating CD34- cells, we specifically monitored
the migration of CD34+ cells by staining the migrated
CD34+ cells with anti-CD34 mAb and analyzing them by
flow cytometry. Maximum migration was observed at MIP-3ß
concentrations between 200 and 2000 ng/ml (Fig. 1A). Most of
the time, 10 to 15% of input BM CD34+ cells were attracted
to MIP-3ß at 200 ng/ml (Fig. 1B). SDF-1, at an optimum
concentration (200 ng/ml, as determined previously (3)), attracted
approximately 50% of input CD34+ cells (Fig. 1B). MIP-3ß in a negative gradient showed inhibitory
effects on CD34+ cell migration induced by a positive
gradient of this chemokine (Table I). At
20 ng/ml concentration in the upper chamber, it greatly decreased
CD34+ cell migration induced by 200 ng/ml MIP-3ß in the
lower chamber (Table I). Like SDF-1, it showed no significant
chemokinetic activity for CD34+ cells, which is defined as
random movement observed under zero concentration gradient with the
same amount of chemoattractants in both chambers (3). Most chemokines
show transient actin polymerization in cells. Regulation of actin
polymerization by chemoattractants is believed to be important in many
biologic processes, including cell movement. We treated BM
CD34+ cells with MIP-3ß and observed that it induced
transient actin polymerization in these cells (data not shown).
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C) since it is difficult to
obtain enough CD34+ cells for more quantitative Northern
blot analysis. CCR7 mRNA was detected in CD34+ cells
responding to MIP-3ß as well as in the input CB CD34+
cells used for chemotaxis (Fig. 1C). MIP-3ß attracts macrophage progenitors in BM and CB CD34+ cells
We performed colony-forming assays to examine chemotactic activity
of MIP-3ß on HPC, because not all CD34+ cells are HPC and
able to form colonies in semisolid culture medium containing
appropriate growth and differentiation factors. Another reason for
analyzing colony formation was to determine whether MIP-3ß had
specificity for certain types of HPC. We assayed the migrated
CD34+ cells in methylcellulose media containing growth
factors (GM-CSF, SLF, IL-3, and EPO for assaying CFU-GEMM; GM-CSF,
IL-3, and EPO for CFU-GM and BFU-E). Surprisingly, MIP-3ß attracted
mainly CFU-GM in BM CD34+ cells. The chemotactic activity
for other BM progenitors such as BFU-E and the more immature CFU-GEMM
was weak and not significant (Table II).
At high concentrations of MIP-3ß (500–2000 ng/ml), a significant
chemoattraction of CB BFU-E and CFU-GEMM by MIP-3ß was also observed
in addition to that seen for CFU-GM (Table II). However, attraction of
CB CFU-GM to MIP-3ß was greater than that for CB CFU-GEMM and BFU-E.
Maximum chemoattraction of BM CFU-GM was observed at MIP-3ß
concentrations between 200 and 2000 ng/ml. This was in good agreement
with the results shown in Figure 1A for CD34+
cells.
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A) and CB (Fig. 2B). In contrast, colonies formed from the BM and CB
CD34+ cells attracted to MIP-3ß were quite homogeneous in
morphology, and the size of mature cells in the colonies was quite
large (Fig. 2, C and D). To more precisely
identify the types of colonies, we used cytochemical staining
techniques including Wright-Giemsa or esterase (-naphthyl acetate
esterase and naphthol AS-D-chloroacetate esterase)
staining. Most mature cells in the GM-type colonies formed from the
CD34+ cells migrating in response to MIP-3ß were large
macrophages with developed cytoplasmic structures, which were positive
for -naphthyl acetate esterase and negative for naphthol
AS-D-chloroacetate esterase (Fig. 2, E,
F, G, and H). There were no apparent
differences in the morphology of mature cells from the migrated CB and
BM CD34+ cells in response to MIP-3ß. Other types of
mature cells such as neutrophils were frequently found (e.g., 58% CB
granulo/monocytic colonies) in colonies formed from the input
CD34+ cells, but not found from the CD34+ cells
attracted to MIP-3ß in a greater than background level. This
demonstrated specificity of this chemokine for progenitors of the
macrophage lineage among HPC of granulo/monocytic lineages.
To further verify the fact that MIP-3ß attracted macrophage, but not
granulocyte progenitors, we assayed the migrated BM CD34+
cells in agarose colony culture assay in the presence of only M-CSF to
specifically detect M-CSF-responsive CFU-M, or in the presence of G-CSF
to detect G-CSF-responsive CFU-G progenitors (13). M-CSF has been shown
to exert differentiation and proliferation effects on cells of the
mononuclear phagocyte lineages, and in the presence of M-CSF alone, all
colonies formed in agarose/agar media containing 10% heat-inactivated
FBS are reported to be -naphthyl acetate esterase-positive monocyte
progenitors (CFU-M) (13, 22). On the other hand, G-CSF alone in
agarose/agar medium containing heat-inactivated FCS (10%) stimulates
predominantly formation of pure neutrophil granulocyte colonies, which
are mostly positive for naphthol AS-D-chloroacetate
esterase (13, 23, 24). The BM CD34+ cells migrating in
response to MIP-3ß formed colonies in the presence of M-CSF (Fig. 3). However, in the presence of G-CSF,
few colonies formed from the migrated CD34+ cells (Fig. 3).
In contrast, CD34+ cells attracted to SDF-1 formed colonies
in both G-CSF-containing and M-CSF-containing agarose culture media.
These data support the finding that MIP-3ß attracted mainly
macrophage, but not granulocyte progenitors, while SDF-1 attracted both
types of progenitors.
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Northern blot analysis revealed that MIP-3ß mRNA is expressed in
several lymphoid organs, including thymus, intestines, and lymph nodes,
but not BM (6, 7). Activated macrophages have also been reported to
express mRNA for MIP-3ß (7). We examined the possibility that
MIP-3ß mRNA might be expressed in the BM environment upon induction.
Primary BM stromal cells were derived from BM aspirates. Confluent BM
stromal cells, containing mainly fibroblast-like cells, were treated
with LPS, IFN-, LPS plus IFN-, or TNF-, and analyzed for
expression of MIP-3ß message. Consistent with previous Northern blot
analysis data (6, 7), no MIP-3ß mRNA was detected in resting BM
stromal cells (Fig. 4). However, either
LPS, IFN-, or TNF- alone induced expression of MIP-3ß mRNA and
IFN- increased the LPS-dependent mRNA expression, demonstrating that
the BM environment can be induced to express MIP-3ß. In contrast,
G-CSF and SLF did not induce expression of MIP-3ß mRNA. We performed
Northern blot analysis to examine the induction of MIP-3ß mRNA in a
more quantitative way from control cells, cells stimulated with 1, 5,
and 25 µg/ml LPS; 5, 20, and 100 ng/ml TNF-; or 20, 200, and 1000
U/ml IFN-. In two of three experiments, no mRNA expression was
detected for MIP-3ß, even though expression of
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) demonstrated adequate
loading of RNA in each of the lanes. In only one of the three
experiments did we detect any MIP-3ß mRNA expression, and this was
only with cells stimulated with 25 µg/ml LPS. Thus, the induction of
MIP-3ß mRNA by LPS, TNF-, or IFN- was not reproducibly detected
by Northern blot analysis, suggesting that the induction of MIP-3ß
mRNA is low (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/LARC (7, 14, 16, 17),
CKß-6/MPIF-2/Eotaxin-2 (18, 19), CKß-7/MIP-4 (20), CKß-8/MPIF-1
(18), CKß-10/MCP-4 (21), and CKß-12/IL-10-inducible chemokine
(GenBank accession numbers: U91746 and AB007454) that lacked
chemotactic activity for CD34+ cells, it has been reported
that MIP-1, MIP-1ß, IL-8, MCP-1, RANTES, and eotaxin were also
devoid in chemotactic activity for CD34+ cells (1). Thus,
MIP-3ß has a unique and rare chemotactic activity among CC
chemokines. Chemoattraction by MIP-3ß is highly specific to subtypes
of myeloid progenitors in BM and CB CD34+ cells. The
mechanisms underlying differences in chemotactic specificity between
SDF-1 and MIP-3ß are not known. The broad chemotactic spectrum of
SDF-1 for not only CFU-GEMM, BFU-E, and CFU-GM, but also CFU-G and
CFU-M, suggests the ubiquitous expression of CXCR4, the receptor for
SDF-1, on these HPC. We speculate that distribution of EBI1/BLR2/CCR7,
the receptor for MIP-3ß, might be more restricted to subsets of HPC
such as CFU-M. Unfortunately, until one can phenotypically define
subsets of myeloid progenitors such as CFU-GEMM, BFU-E, CFU-GM, CFU-G,
and CFU-M by a means that clearly distinguishes one progenitor type
from another, it will be difficult to determine selective receptor
distribution on these different progenitor cell types.
MIP-3ß is believed to be either present at a very low level or not
present under normal conditions in BM, because no MIP-3ß mRNA is
detected by RT-PCR and Northern blot analysis in BM. We have now shown
that LPS, IFN-, or TNF- induces mRNA expression of MIP-3ß in BM
stromal cells. Thus, it is reasonable to speculate that MIP-3ß may
influence trafficking of CFU-M to/from BM under inflammatory
conditions.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Hal E. Broxmeyer, Department of Microbiology/Immunology and Walther Oncology Center, Indiana University School of Medicine, Building R4, Rm. 302, 1044 West Walnut Street, Indianapolis, IN 46202.
3 Abbreviations used in this paper: HPC, hemopoietic progenitor cells; BFU-E, burst-forming unit erythrocyte; BM, bone marrow; CB, cord blood; CHO, Chinese hamster ovary; EPO, erythropoietin; G, granulocyte; GEMM, granulocyte, erythrocyte, macrophage, and megakaryocyte; GM, granulocyte macrophage; M, macrophage; MCP, monocyte chemotactic protein; MIP, macrophage-inflammatory protein; MPIF, myeloid progenitor inhibitory factor; PE, phycoerythrin; rhu, recombinant human; SDF-1, stromal cell-derived factor-1; SLF, steel factor; LARC, liver and activation-regulated chemokine.
Received for publication December 19, 1997. Accepted for publication May 1, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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