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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2791-2797
Mast Cell Migratory Response to Interleukin-8 Is Mediated Through
Interaction With Chemokine Receptor CXCR2/Interleukin-8RB
By
Gunnar Nilsson,
Judy A. Mikovits,
Dean D. Metcalfe, and
Dennis D. Taub
From the Department of Genetics and Pathology, Uppsala University,
Uppsala, Sweden; Science Applications International
Corporation-Frederick, National Cancer Institute-Frederick Cancer
Research and Development Program, Frederick, MD; Laboratory of Allergic
Diseases, National Institute of Allergy and Infectious Diseases,
National Institutes of Health (NIH), Bethesda, MD; and Clinical
Immunology Section, Laboratory of Immunology, National Institute on
Aging, NIH, Baltimore, MD.
 |
ABSTRACT |
To explore the role of chemokines in mast cell chemotaxis and
accumulation at sites of inflammation, we first investigated the
response of human mast cells to 18 different chemokines by induction of
intracellular calcium mobilization in the human mast cell line, HMC-1.
Only a subgroup of CXC chemokines defined by the conserved sequence
motif glutamic acid-leucine-arginine (ELR) tripeptide motif, which
included interleukin-8 (IL-8), growth-regulated oncogene  (GRO),
neutrophil-activating peptide-2 (NAP-2), and epithelial cell-derived
neutrophil activating peptide-78 (ENA-78), induced calcium flux in the
cells. These observations suggested that the receptor CXCR2 (IL-8RB)
should be expressed on the surface of these cells. Using the RNAse
protection assay, CXCR2 mRNA, but not CXCR1 (IL-8RA) mRNA expression
was detected in HMC-1 cells. Flow cytometry analysis documented the
surface expression of CXCR2. A binding analysis performed with
125I-IL-8 determined that there were approximately 3,600 high affinity IL-8 binding sites per HMC-1 cell, with a calculated
kd of 1.2 to 2 nmol/L. The activity of this receptor was
further explored using IL-8, which was found to induce dose-dependent
chemotactic and haptotactic responses in both HMC-1 cells and in vitro
cultured human cord blood-derived mast cells. These results show the
expression of functional CXCR2 receptors on the surface of human mast
cells, which may play an important role in mast cell recruitment during the genesis of an inflammatory response.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
MAST CELLS ARE multifunctional effector
cells of the immune system.1,2 A local accumulation of mast
cells has been described in such diverse pathologic conditions as
allergic inflammation, parasitic infections, scleroderma, rheumatoid
arthritis, interstitial cystitis, and in transplanted tissues
undergoing rejection.3 Directional migration of
inflammatory cells is presumably based on the local production of
chemotactic factors. Reports that stem cell factor (SCF), transforming
growth factor- (TGF-), and the anaphylatoxins, C3a and C5a, are
mast cell chemoattractants4-8 have provided support for
this hypothesis.
The chemokines are a superfamily of proinflammatory cytokines
associated with inflammatory pathology. They play a critical role in
the selective recruitment of leukocytes by acting as
chemotaxins.9 The chemokines are classified into the four
subfamilies C, CC, CXC, and C(X)3C, based on the number and
arrangement of conserved cysteine residues.10 The
prototypic CXC chemokine is interleukin-8 (IL-8), which was originally
described as a monocyte-derived factor that attracts
neutrophils.11,12 Several other CXC chemokines are also
potent neutrophil chemoattractants. These include growth-regulated oncogene  (GRO), epithelial cell-derived neutrophil activating peptide-78 (ENA-78), and neutrophil-activating peptide-2 (NAP-2). In
contrast, the CC chemokines preferentially act on monocytes, lymphocytes, natural killer (NK) cells, basophils, and eosinophils.
Chemokines mediate their effects by binding to seven
transmembrane-spanning, G protein-coupled receptors.13,14
Five CXC-receptors (CXCR) and nine CCR have been described to date.
Cells of hematopoietic origin express unique, but overlapping, subsets
of these chemokine receptors. Chemokine receptor subtypes in turn are
selective for unique, but overlapping, subsets of chemokines. CXCR1 and
CXCR2 have been shown to bind IL-8 with high affinity.15-17
CXCR1 is specific for IL-8, while CXCR2 binds IL-8, as well as NAP-2,
GRO, and ENA-78.18-20 IL-8R is expressed on neutrophils,
monocytes, NK cells, and T lymphocytes.21-23
In the current study, we initially screened the response of the human
mast cell line HMC-1 to 18 different CXC, CC, and C chemokines. The
results led us to characterize the expression of CXCR2 on the surface
of HMC-1 cells and the migratory response of both HMC-1 cells and in
vitro developed human cord blood-derived mast cells to IL-8.
| |
MATERIALS AND METHODS |
Cell cultures.
The human mast cell line, HMC-1 (kindly provided by Dr J.H.
Butterfield, Mayo Clinic, Rochester, MN)24,25
was cultured in Iscove's modified Dulbecco's medium (IMDM)
supplemented with 10% heat inactivated fetal calf serum (FCS), 2 mmol/L L-glutamine, 100 IU/mL penicillin, 50 µg/mL streptomycin, and
1.2 mmol/L -thioglycerol. The cells were passaged every 3 to 4 days.
Human cultured mast cells were obtained by placing umbilical cord blood
cells in complete RPMI 1640 supplemented with 10% heat-inactivated FCS
and 100 ng/mL SCF (R & D Systems, Minneapolis, MN) as
described.26
Intracellular [Ca2+] measurements.
HMC-1 cells (5 × 106/mL) were incubated in RPMI
medium with 1% FCS, containing 2.5 µmol/L FURA-2 AM for 60 minutes
at 30°C. The cells were washed and resuspended at 1 × 106/mL RPMI 1640 with Ca2+ and Mg2+
and 1% FCS. A total of 2 mL of the cell suspension was placed in a
continuously stirred cuvette at 37°C in a fluorimeter (Photon Technology Inc, South Brunswick, NJ). Fluorescence was monitored at
 ex1 = 340 nm, ex2 = 380 nm, and
em = 510 nm, and the data presented as the relative
ratio of fluorescence excited at 340 and 380 nm. Data were collected
every 500 ms. The following chemokines were tested: Lymphotactin, IL-8,
monocyte chemotactic protein (MCP)-3, GRO, NAP-2,
ENA-78, and interferon-inducible protein (IP)-10
(Peprotech, Rocky Hill, NJ); RANTES, macrophage
inflammatory protein (MIP)-1, MIP-1, and
MCP-1 (Genzyme, Cambridge, MA); HCC-1 and I-309 (R & D Systems,
Minneapolis, MN); and platelet factor-4 (PF-4) (Sigma Chemical
Co, St Louis, MO). Eotaxin was a kind gift from Dr O. Yoshi (Shionogi Institute for Medical Science, Osaka,
Japan), MCP-2 was a kind gift from Dr J. Van Damme (University of
Leuven, Leuven, Belgium), T-cell activation
(TCA)3 was a kind gift from Dr M.E. Dorf (Harvard
Medical School, Boston, MA) and MIG
(monokine induced by interferon- ) was a kind gift from Dr J.M.
Farber (NIAID, NIH, Bethesda, MD).
RNAse protection analysis.
Detection of human chemokine receptor message expression was
performed with an RNAse protection analysis system (RiboQuant; Pharmingen, San Diego, CA). Two multiprobe template sets (hCR5 and hCR6) were used for in vitro transcription reactions using T7
polymerase to direct synthesis of high specific activity
[32P]-labeled antisense RNAs that hybridize with human
RNAs encoding CXCR1, CXCR2, CXCR3, CXCR4, BLR-1, BLR-2, V28, and two
housekeeping control gene products L32 and glyceraldehyde-3-phosphate
dehydrogenase (GAPDH); and CCR1, CCR3, CCR4, CCR5, TERI,
CCR2a, CCR2b, L32, and GAPDH, respectively. Templates were transcribed
using a Maxiscript Kit (Ambion, Austin, TX) in the presence of a
32P-uridine triphosphate (UTP) (800 Ci/mmol;
NEN, Beverly, MA). Total RNA was isolated using Trizol (Life
Technologies, Gaithersburg, MD) according to the manufacturer's
instructions. RNAse protection analysis of 20 µg total RNA was
performed after overnight hybridization at 60°C with 1.5 × 106 cpm of 32P-hCR6 using the RPAII Kit
(Ambion) according to the manufacturer's instructions. Protected
fragments were precipitated and electrophoresed on 6% sequencing gels.
Gels were dried and scanned on a phosphorimager (Molecular Dynamics,
Palo Alto, CA). Dried gels were photographed on XAR-5 film (Kodak, KEBO
Lab, Spånga, Sweden) at  70°C.
Flow cytometric analysis.
HMC-1 cells were stained with monoclonal antibodies against CXCR1
or CXCR2 using antibodies purchased from R & D Systems
conjugated to either fluorescein isothiocyanate (FITC) or
phycoerythrin (PE). Flow cytometric analysis was
performed on a FACStar plus (Becton Dickinson, Mountain View, CA).
Chemokine binding studies.
For binding assays, 5 × 105 cells per mL were
incubated in phosphate-buffered saline (PBS) with
125I-labeled IL-8 ligand (0.2 nmol/L) (specific activity,
2,200 Ci/mmol; New England Nuclear, Boston, MA) and varying
concentrations of unlabeled ligands at 4°C for 1 hour. The
incubation was terminated by removing aliquots from the cell suspension
and separating cells from buffer by centrifugation through a
silicone/paraffin oil mixture as described.23 Nonspecific
binding was determined in the presence of 1 µmol/L unlabeled ligand.
The binding data were curve fit with the computer program LIGAND
(Biosoft, St Louis, MO) to determine the affinity (KD), number of
sites, and nonspecific binding.
Chemotaxis assay.
Mast cell migration was examined using a 48-well microchemotaxis assay
as described.27 Briefly, various concentrations of chemokine were placed in the lower compartment of a 48-well
microchemotaxis chamber. Mast cells (2 to 5 × 106
cells/mL) were then placed in the upper compartment. The upper and
lower compartments of the chamber were separated by a 5 µm polycarbonate filter coated with fibronectin (Sigma Chemical
Co).5 The chambers were incubated for 4 hours at 37°C,
a time period over which chemokine equilibrium between the upper and
lower chambers is optimally achieved. Filters were then scraped,
washed, fixed with methanol, and stained with Diff-Quik.
Cell migration was measured by counting the number of cells attached to
the lower surface of the filter in three high-power fields (HPF). Each
concentration of chemokine was tested in either triplicate or sets of
six wells. The results were expressed as the average of the number of
migrating cells per three HPF (±standard error of the mean
[SEM]). A checkerboard analysis of mast cell motility was conducted
according to the method of Zigmond and Hirsch.28
For determination of haptotactic response of HMC-1 cells to IL-8,
polycarbonate filters were precoated with Matrigel (Collaborative Biomedical Products, Bedford, MA), washed, dried, and incubated with
either medium, IL-8, or PF-4 at the designated concentrations. After a
24-hour incubation, the filters were gently washed, dried, and tested
in microchemotaxis chambers with HMC-1 cells.
Treatment with pertussis toxin.
Pertussis toxin (Sigma Chemical Co) treatment was performed by
incubating 2.5 × 106 cells/mL for 90 minutes at
37°C with 0.1 or 1 µg/mL of the toxin in complete medium. After
incubation, the cells were washed and resuspended in fresh medium
before use.
| |
RESULTS |
Analysis of chemokine-induced [Ca2+]i in
HMC-1 cells.
Changes in [Ca2+]i are classically associated
with chemokine activation of cells and provide a mechanism by which
receptor engagement and response specificity may be
examined.14 HMC-1 cells were therefore tested for
[Ca2+]i after treatment with chemokines of
the C, CC, and CXC families (Table 1). Of
the chemokines tested, only CXC chemokines defined by the conserved
sequence glutamic acidleucine-arginine (ELR) tripeptide motif,
namely IL-8, GRO, NAP-2, and ENA-78, induced an intracellular
calcium flux in the HMC-1 cells. The kinetics of the responses to IL-8,
ENA-78, GRO, and NAP-2 was almost indistinguishable (Fig 1A). The magnitude of the peak of
[Ca2+]i was dependent on the ligand
concentration tested (Fig 1B). The 50% effective dose
(ED50) for IL-8, ENA-78, GRO, and NAP-2 was approximately 5 ng/mL, 10 ng/mL, 10 ng/mL, and 25 ng/mL,
respectively.
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| Fig 1.
Calcium mobilization by IL-8, GRO, NAP-2, and ENA-78
in HMC-1 cells. (A) Kinetics: agonists were added at the time indicated
by the arrows. The identity and concentration are indicated to the
right of each arrow. (B) Concentration dependence: calcium mobilization
was measured in the cells stimulated as indicated. The amplitude
of the peak change in fluorescence is shown as a function of the
chemokine concentration. Results from one cell experiment are shown.
Similar results were obtained in three independent experiments.
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Activation of G protein-coupled receptors typically induces a
refractory period during which the receptor cannot transduce signals
when stimulated a second time with same or other agonists, a phenomenon
known as "desensitization." IL-8, ENA-78, GRO, and NAP-2 all
induce homologous desensitization in HMC-1 cells
(Fig 2 and data not shown). Furthermore,
IL-8 caused heterologous desensitization of ENA-78-, GRO-, and
NAP-2-induced activation of HMC-1 cells (Fig 2). In contrast, ENA-78,
GRO, or NAP-2, when added first, reduced, but did not abolish, the
calcium signal induced by IL-8 (Fig 2). No cross-desensitization of the
response to IL-8 was detected when RANTES or MIG was used as the first
agonist (data not shown).
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| Fig 2.
Desensitization of calcium transients in HMC-1 cells.
Relative fluorescence was monitored from FURA-2-loaded cells before
and during sequential addition of CXC chemokines at the times indicated
by the arrows. The identity of each stimulus is indicated to the right
of each arrow. The concentrations used were 10 ng/mL IL-8 and GRO
and 25 ng/mL NAP-2 and ENA-78. Each tracing shown is from a single
experiment and is representative of at least two separate
experiments.
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Detection of mRNA and surface expression of CXCR2 on HMC-1 cells.
The results from these studies on chemokine-induced calcium flux
suggested the expression of IL-8 receptors on HMC-1 cells. Two IL-8R
have been described, CXCR1 and CXCR2. Thus, CXC receptor expression in
HMC-1 cells was first analyzed at the level of message using Pharmingen
hCR6 multiprobes in an RNAse protection assay (RPA). In addition to the
housekeeping gene GAPDH (96), a protected fragment of 321 was detected,
reflecting the presence of the CXCR2 RNA
(Fig 3A). In contrast, CXCR1 mRNA was not
detected. None of the CCRs could be detected using the hCR5 multiprobe
(data not shown). While not shown, HMC-1 cells also expressed RNA for
CXCR4 and hv28.
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| Fig 3.
Expression of IL-8 receptors by HMC-1 cells. (A) CXC
receptor expression was measured at the level of message by RPA. In
addition to the housekeeping gene product GAPDH (96), a protected
fragment for CXCR2 (321) was detected. The two lanes represent two
preparations of HMC-1. (B) CXCR2 expression on the surface of HMC-1
cells analyzed by flow cytometry. The bold histogram shows the
expression of CXCR2; the thin histogram represents isotype control
MoAb. This result is representative of four independent experiments.
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Surface expression of IL-8 receptors was next analyzed by flow
cytometry using monoclonal antibodies (MoAbs) directed against CXCR1 and CXCR2. Expression of CXCR2 could be detected on the surface
of HMC-1 cells, consistent with the previous data (Fig 3B). CXCR1
could not be detected (data not shown).
Characterization of 125I-IL-8 binding sites on HMC-1
cells.
Receptor binding experiments using 125I-IL-8 and HMC-1
cells showed specific binding at 4°C
(Fig 4A). A Scatchard plot analysis of
binding of 125I-IL-8 to HMC-1 cells demonstrated a single
class of approximately 3,600 high-affinity IL-8 binding sites with a
calculated kd of 1.2 to 2 nmol/L (Fig 4A, insert). Bound
125I-IL-8 was displaced by unlabeled IL-8 or GRO, but
not by unlabeled IP-10 or PF-4 (Fig 4B).
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| Fig 4.
Analysis of 125I-IL-8 binding to HMC-1 cells.
(A) A representative equilibrium-binding analysis is shown, and
Scatchard plot transformation of the binding data is presented in the
insert. (B) Concentration-dependent displacement of
125I-IL-8 binding to HMC-1 cells by IL-8 ( ), GRO
( ), IP-10 ( ), and MIG ( ). HMC-1 cells (5 × 105 cells in each tube) were incubated with
125I-IL-8 (0.2 nmol/L) in the presence or absence of
increasing concentrations of unlabeled ligand for 60 minutes at
4°C.
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IL-8-mediated migration of human mast cells.
The migratory response of human mast cells was determined in a
microchemotaxis chamber. HMC-1 cells migrated in response to IL-8 and
GRO in a dose-related manner, but not to PF-4
(Fig 5A). Similarly, IL-8, but not PF-4,
induced migration of in vitro cultured human mast cells (Fig 5B). IL-8
induced maximal migration at 100 ng/mL, with an ED50 of
approximately 1 ng/mL. The ability of IL-8 to stimulate directional
migration (chemotaxis) versus random migration (chemokinesis) was
analyzed using a checkerboard analysis. As shown in
Table 2, IL-8 was found to be chemotactic,
but not chemokinetic for mast cells. Chemokinesis was calculated to be less than 5% of the total migration observed.
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| Fig 5.
Chemotactic effect of IL-8 on HMC-1 cells (A) and in
vitro cultured human mast cells (B). Cells were exposed to various
concentrations of IL-8, GRO, or PF-4, as indicated for 4 hours. The
results are expressed as the number of countable cells per 3HPF (mean ± SEM) (n  5). *P < .05, **P < .01.
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In contrast to chemotaxis, which is defined as migration towards a
gradient of soluble factor, haptotaxis is migration to surface-bound
gradients of the chemoattractant. IL-8 is known to easily bind to
surfaces and has been shown to induce haptotaxis in
neutrophils.29 We therefore investigated whether IL-8
could mediate haptotaxis in mast cells. IL-8 was incubated in different concentrations with polycarbonate filters precoated with extracellular matrix proteins. The filters were then used in a microchemotaxis chamber. IL-8 was found to induce haptotactic migration of HMC-1 cells
in a dose-related manner (Fig 6).
PF-4-coated filters did not promote mast cell migration.
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| Fig 6.
Haptotactic effect of IL-8, but not PF-4, on HMC-1 cells.
The migration of cells was tested on precoated filters exposed to
medium alone or to various concentrations of IL-8 or PF-4. The results
are expressed as the number of countable cells per 3HPF (mean ± SEM)
(n = 3). *P < .05, **P < .01.
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IL-8-induced migration was inhibited by prior treatment of HMC-1 cells
with 100 ng/mL or 1,000 ng/mL of pertussis toxin for 90 minutes
(Table 3). SCF-induced migration, which is
mediated through receptor tyrosine kinase, was not inhibited by similar treatment with the pertussis toxin. This data is consistent with the
conclusion that CXCR2 expressed on mast cells is coupled to Gi protein,
as reported for CXCR2 expressed on neutrophils.30
| |
DISCUSSION |
The data presented show that human mast cells express CXCR2 (Figs 3 and
4) and that the interaction of CXCR2 with its natural ligands, IL-8 and
GRO, induces calcium mobilization (Fig 1) and cell migration (Fig 5A
and B). Although IL-8 is an inflammatory cytokine that is known to
function as a neutrophil chemoattractant and activating factor,
monocytes, NK cells, and T lymphocytes also respond chemotactically to
IL-8.13,21-23,31 Similarly, mast cells are thus also
capable of responding to IL-8-induced signals.
Mast cells accumulate during both acute and chronic inflammation. This
local increase in mast cells is due, at least in part, to the
redistribution and recruitment of neighboring mast cells. One example
of the rapid accumulation of mast cells is the increase in these cells
observed within the intraepithelial cell layer of the nasal mucosa
after local allergen provocation.32 Several factors capable
of attracting human mast cells have been reported. These include SCF,
TGF-, and the anaphylatoxins.5,7,8 However, the only
chemokine reported to induce migration of human in vitro developed mast
cells and pulmonary mast cells was RANTES,5,33 which did
not induce HMC-1 cell migration or calcium influx5 (and
this study). Furthermore, no transcripts for any of the receptors interacting with RANTES were detected in HMC-1 cells, ie, CCR1, CCR3,
CCR4, and CCR5. These results are in agreement with the results of
Hartmann et al,8 who have also reported that CC chemokines
do not promote chemotaxis of HMC-1 cells. Although unresponsive to CC
chemokines, human mast cells, as noted in the current study, do respond
to multiple ELR+ CXC chemokines, ie, IL-8, ENA-78, GRO,
and NAP-2.
Chemokines act via G protein-coupled receptors. With these receptors,
there is typically a refractory period after initial stimulation during
which the receptor cannot transduce signals when stimulated a second
time with the same or other agonists. All of the ELR+ CXC
chemokines tested in this study showed this homologous desensitization. IL-8 also desensitized the calcium response to GRO, ENA-78, and NAP-2 in HMC-1 cells (heterologous desensitization). In contrast, GRO, ENA-78, or NAP-2 given as the first stimuli, reduced, but not
abolished the calcium flux induced by IL-8. This is well described for
the CXCR2 receptor, although the precise mechanism for this effect is
unknown.20 Thus, mast cells and neutrophils respond similarly to CXCR2 agonist treatment.
Surface CXCR2 appears to represent all IL-8 binding sites on HMC-1
cells. CXCR2, but not CXCR1, message was detected in HMC-1 cells, and
CXCR2 protein expression was shown at the single cell level with
specific antibodies and flow cytometry. A Scatchard plot analysis
showed fewer IL-8 binding sites on HMC-1 cells (3,600 binding
sites/cell) than on neutrophils (60,000 binding
sites/cell).18 This IL-8 binding site number on mast
cells is similar to the number estimated on T
lymphocytes.23
Both HMC-1 cells and in vitro cultured human mast cells migrated in
response to IL-8. The number of mast cells of both types migrating to
100 ng/mL of IL-8 (approximately 75/3HPF) is fewer than the number of
mast cells migrating in response to platelet-activating factor or C5a
(approximately 100 to 140/3HPF) (Nilsson et al, submitted). However,
the migration of mast cells to IL-8 (and GRO for HMC-1 cells) was
significant and specific. No migration could be determined to PF-4 used
as a chemokine control.
In summary, CXCR2 is expressed on HMC-1 cells and IL-8 is a potent
chemotaxin for human mast cells. These observations may be relevant to
the understanding of mast cell migration in vivo, as IL-8 is known to
be elevated in several inflammatory diseases, where an increase in mast
cells have been described, including rheumatoid arthritis, inflammatory
bowel diseases, and psoriasis.13,34 Mast cell migration
towards IL-8 appears thus to represent an important mechanism in the
recruitment of mast cells to sites of tissue inflammation.
| |
ACKNOWLEDGMENT |
We thank Dr P.M. Murphy (NIH, Bethesda, MD) for advice on the
intracellular calcium measurements.
| |
FOOTNOTES |
Submitted August 18, 1998; accepted December 22, 1998.
Supported in part by grants from the Swedish Cancer Society, the
Swedish Foundation for Health Care Sciences and Allergy Research, the Swedish Heart Lung Foundation, King Gustav V:s 80 Year
Foundation, Konsul Th C Bergh Foundation, and Ollie and Elof Ericssons Foundation.
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 Gunnar Nilsson, PhD, Unit of
Pathology, Department of Genetics and Pathology, Uppsala University,
S-751 85 Uppsala, Sweden; e-mail: Gunnar.Nilsson{at}patologi.uu.se.
| |
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