|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2240-2248
Eotaxin Induces a Rapid Release of Eosinophils and Their
Progenitors From the Bone Marrow
By
Roger T. Palframan,
Paul D. Collins,
Timothy J. Williams, and
Sara
M. Rankin
From the Leukocyte Biology Section, Biomedical Sciences Division,
Imperial College School of Medicine at the National Heart and Lung
Institute, London, UK.
 |
ABSTRACT |
The CC-chemokine eotaxin is a potent eosinophil chemoattractant that
stimulates recruitment of eosinophils from the blood to sites of
allergic inflammation. Mobilization from the bone marrow is an
important early step in eosinophil trafficking during the allergic
inflammatory response. In this paper we examine the potential of
eotaxin to mobilize eosinophils and their progenitors from bone marrow.
Eotaxin stimulated selective, dose-dependent chemotaxis of guinea pig
bone marrow eosinophils in vitro. Intravenous injection of eotaxin (1 nmol/kg) into guinea pigs in vivo stimulated a rapid blood eosinophilia
(from 3.9 ± 1.2 to 28 ± 9.9 × 104
eosinophils/mL at 30 minutes) and a corresponding decrease in the
number of eosinophils retained in the femoral marrow (from 9.0 ± 0.8 to 4.8 ± 0.8 × 106 eosinophils per
femur). To show a direct release of eosinophils from the bone marrow an
in situ perfusion system of the guinea pig femoral bone marrow was
developed. Infusion of eotaxin into the arterial supply of the perfused
femoral marrow stimulated a rapid and selective release of eosinophils
into the draining vein. In addition, eotaxin stimulated the release of
colony-forming progenitor cells. The cytokine interleukin-5 was
chemokinetic for bone marrow eosinophils and exhibited a marked
synergism with eotaxin with respect to mobilization of mature
eosinophils from the femoral marrow. Thus, eotaxin may be involved in
both the mobilization of eosinophils and their progenitors from the
bone marrow into the blood and in their subsequent recruitment into sites of allergic inflammation.
| |
INTRODUCTION |
EOSINOPHILS ACCUMULATE in high numbers
during allergic reactions, such as allergic asthma and rhinitis. There
is considerable evidence that links the accumulation and activation of
these cells with tissue injury and lung dysfunction.1-3
In experiments designed to identify local chemical signals stimulating
eosinophil recruitment in allergic inflammatory reactions, we purified
and sequenced a CC-chemokine, eotaxin, from bronchoalveolar lavage
fluid of allergen-challenged sensitized guinea pigs.4,5 The
eotaxin gene has since been cloned from guinea pig,6,7 mouse,8,9 and human cells.10,11 Eotaxin is a
potent eosinophil chemoattractant which signals via CCR3, a chemokine
receptor highly expressed on eosinophils.4,5,8-12
There is evidence that eotaxin has an important local role in
stimulating the recruitment of eosinophils from blood microvessels into
the tissue at sites of allergic inflammation.4-7,9-11,13,14 Because circulating numbers of eosinophils are normally low the extent
of recruitment is also dependent on factors that regulate the numbers
of eosinophils in the blood. We observed that intravenously administered interleukin-5 (IL-5) mobilized a pool of eosinophils from
guinea pig bone marrow, producing a rapid blood
eosinophilia.15 This effect correlated with a marked
increase in local eosinophil recruitment induced by
intradermally injected eotaxin.15 We have suggested
that mobilization from the bone marrow is an important early step in
eosinophil trafficking during the allergic inflammatory response.16
Although the molecular mechanisms involved in mobilization of
leukocytes from the bone marrow are poorly understood, it is clear that
migration of leukocytes from the marrow hematopoietic compartment into
the sinusoidal lumen is essential for this process.17 Therefore, it is possible that factors that stimulate a migratory response in leukocytes may induce their mobilization from the bone
marrow.18 Factors that stimulate leukocyte migration do so
by inducing either a chemotactic or chemokinetic response. IL-5, which
mobilizes bone marrow eosinophils, has been shown to induce eosinophil
chemokinesis,19,20 but has relatively weak efficacy as a
local eosinophil chemoattractant in vivo15 or as a
chemotactic agent in vitro.21-24 Eotaxin, in contrast, is a
potent eosinophil chemoattractant in vivo and in
vitro.4-6,10-12,14,15 Therefore we have investigated
whether eotaxin, in addition to recruiting eosinophils into tissue, can
mobilize eosinophils from the bone marrow.
An increase in eosinophil progenitor cells has previously been reported
in the blood of atopics,25 in asthmatics during exacerbation,26,27 and in nasal polyp tissue.28
Furthermore, it has been shown previously that some chemokines can
stimulate the mobilization of hematopoietic progenitor cells from the
bone marrow.29-31 However, there have been no reports of
factors that selectively release eosinophil progenitors. We have
therefore investigated whether eotaxin stimulates the mobilization of
eosinophil progenitors from the bone marrow.
In this paper we show that eotaxin has a potent and selective effect in
mobilizing bone marrow eosinophils in the guinea pig. Marked synergism
between eotaxin and IL-5 was observed. In addition, colony-forming
progenitors were mobilized in response to eotaxin, but not IL-5. In
contrast, differentiation of the progenitors into eosinophils was
stimulated by IL-5, but not by eotaxin.
The eosinophil is a minority cell type in the circulation (normally 1%
to 2% of blood leukocytes in humans). Despite this, high numbers of
eosinophils are able to accumulate at sites of allergic inflammation,
which necessitates mechanisms to increase blood levels of these cells
acutely. We suggest that these cells can be mobilized from the large
reserve of eosinophils that are known to be present in the human bone
marrow.32 The results presented here represent the first
demonstration of a chemokine, eotaxin, that stimulates the selective
release of eosinophils and their progenitors from the bone marrow.
| |
MATERIALS AND METHODS |
Animals.
Male Dunkin-Hartley guinea pigs (250 to 350 g) were obtained from
Harlan Olac Ltd (Bicester, UK).
Materials.
Synthetic guinea pig eotaxin was a gift from Drs Glen Andrews and Henry
Showell (Pfizer Inc, Groton, CT). Human recombinant IL-5
was a gift from Dr T.N.C. Wells (GlaxoWellcome Ltd, Geneva, Switzerland). Penicillin-streptomycin (pen-strep), Iscove's modified Dulbecco's medium (IMDM), fetal calf serum (FCS), phosphate-buffered saline (PBS), Hank's Balanced Salt Solution (HBSS), and Hepes buffer
were purchased from Life Technologies (Paisley, UK). Hypnorm (fentanyl
citrate, 0.315 mg/mL; fluanisone, 10 mg/mL) was purchased from Janssen
Pharmaceutical Ltd (Oxford, UK). Hypnovel (Midazolam, 5 mg/mL) was
purchased from Roche (Welwyn, UK). Expiral (sodium pentobarbitone, 200 mg/mL) was purchased from May and Baker (Dagenham, UK). Methocult GF
H4534 medium, a Stem Cell Technologies product (Vancouver, Canada), was
purchased from Metachem diagnostics Ltd (Northampton, UK). EasyLyse
erythrocyte lysis kits were purchased from Universal Biologicals
(London, UK). Transwell inserts with 3-µm pores were purchased from
Millipore (Watford, UK). Methylene blue and eosin were purchased from
Merck (Dagenham, UK). All other reagents were purchased from Sigma
Chemical Co (Poole, UK). Kimura's stain for positive identification of
eosinophils was prepared as previously described.33
Modified Krebs-Ringer bicarbonate buffer of the following composition
was used in perfusion experiments: D-Glucose, 10 mmol/L; CaCl2, 3.33 mmol/L; MgCl2.6H2O,
0.49 mmol/L; KCl, 4.56 mmol/L; NaCl, 120 mmol/L;
Na2HPO4, 0.7 mmol/L;
NaH2PO4, 1.5 mmol/L; and NaHCO3, 24 mmol/L. The buffer was supplemented with 4% Ficoll T-70 and 0.1%
bovine serum albumin (BSA) and gassed with 95% O2 and 5%
CO2.
Preparation of guinea pig femoral marrow leukocytes.
HBSS was prepared containing 30 mmol/L Hepes; 0.25% BSA, pH 7.4; with
(assay buffer) or without (cell buffer)
Ca2+/Mg2+. Femurs were isolated from guinea
pigs immediately after killing and the ends removed. The femoral shaft
was flushed with 5 mL of cell buffer (containing 10 U/mL heparin).
Displaced cells were gently resuspended using a syringe fitted with a
21G needle. Cells were then centrifuged (200g, 7 minutes,
20°C) and the cell pellet resuspended in 1 mL of cell buffer.
Erythrocytes were removed using hypotonic shock lysis (addition of 10 mL of 0.2% NaCl followed by 10 mL of 1.6% NaCl to restore
isotonicity). After centrifugation (200g, 7 minutes, 20°C)
the leukocyte pellet was resuspended in assay buffer. Total nucleated
leukocyte numbers were determined by counting Kimura-stained samples in
an improved Neubauer hemacytometer.
Transwell chemotaxis assay.
Guinea pig femoral marrow leukocytes were prepared as described above.
For some experiments cells were preincubated with IL-5 for 15 minutes
at 37°C. Bone marrow leukocytes (3 × 106 cells in 0.2 mL of assay buffer) were placed in the upper chamber of Transwell
filters (3-µm pore diameter) that were in turn placed in individual
wells of a 24-well cell culture plate (lower chamber) containing 0.3 mL
of assay buffer to which eotaxin (0 to 10 nmol/L) had been added. The
chambers were incubated for up to 60 minutes at 37°C. Cells migrating
into the bottom chamber were counted using a fluorescence-activated
cell sorter (FACS) flow cytometer (FACScan; Becton Dickinson, Mountain
View, CA), with relative cell counts obtained by acquiring events for a
set time period of 60 seconds. This counting method was highly
reproducible and enabled gating on the different leukocyte populations
and the exclusion of debris. Counts obtained in this way closely
matched those obtained by light microscopy.
Measurement of blood eosinophilia in vivo.
Guinea pigs were sedated with Hypnorm (0.2 mL intramuscularly
[i.m.]). Eotaxin (1 nmol kg 1) or
PBS/0.1% low endotoxin BSA, was injected intravenously (IV) via the
marginal ear vein. Peripheral blood samples (100 µL) were collected
from the marginal ear vein into heparin (10 U/mL) before and at 5, 15, 30, 60, and 120 minutes after injection of eotaxin or vehicle.
Erythrocytes were lysed using EasyLyse reagents. Leukocytes were washed
once with PBS and resuspended in Kimura's stain before counting in an
improved Neubauer hemacytometer (greater than 200 leukocytes per
sample). Nucleated Kimura-positive leukocytes were recorded as
eosinophils. After 120 minutes, the guinea pigs were killed with
Expiral (1.5 mL intraperitoneally) and the right femur was removed.
Femoral marrow leukocytes were prepared as described above. Total
nucleated leukocyte numbers were determined in an improved Neubauer
hemacytometer and differential cell counts obtained from cytocentrifuge
preparations stained with methylene blue and eosin.
Perfusion of the guinea pig femoral bone marrow in situ.
Guinea pigs were anesthetized with Hypnorm (0.8 mL i.m.) and Hypnovel
(0.4 mL i.m.). The right external iliac artery and vein were exposed.
The following arteries and corresponding veins were ligated with 5/0 braided silk suture: caudal abdominal artery, superficial iliac circumflex artery, and pudendoepigastric trunk. Heparin was administered IV via the marginal ear vein (1,000 U/kg) and
the animal was killed with Expiral (250 mg/kg by cardiac puncture). Cannulae (polyethylene, 0.8-mm outside diameter; Portex, London, UK)
were immediately inserted into the external iliac artery and vein and
pushed down under the inguinal ligament into the femoral artery and
vein. Cannulae were tied in with 5/0 braided silk suture.
Modified Krebs-Ringer bicarbonate buffer (37°C) was perfused (3.4 mL/min) via the arterial cannula and removed from the venous cannula
using a Miniplus peristaltic pump (Anachem, Luton, UK). Perfusion pressure was monitored using a transducer located proximal to
the arterial cannula. Agents were administered in vehicle (PBS/0.1% BSA) in pulses of 10- or 30-minute durations to gain information on
kinetics and conserve reagents. Perfusate fractions were collected over
periods of 10 minutes, centrifuged (300g, 10 minutes, 20°C), and the cell pellet resuspended in Kimura's stain. Nucleated
leukocytes and Kimura-positive eosinophils were counted in an improved
Neubauer hemacytometer. In some experiments, cytocentrifuge (Shandon
Cytospin II) preparations of cells were collected and
stained with methylene blue and eosin.
Colony-forming unit (CFU) assay.
The femoral bone marrow was perfused for 60 minutes with a
10-minute infusion (t = 0 to 10 minutes) of either 3 nmol/L eotaxin or vehicle (as in Fig 3A). The perfusate
was collected and centrifuged (300g, 10 minutes, 20°C), and
the cell pellet resuspended in IMDM (containing 100 U/mL pen-strep and
30% FCS). Of the total leukocytes released, 5 × 105 were
added to 1.5 mL of Methocult GF H4534 medium of the following composition: 0.9% methylcellulose in IMDM, 30% FCS, 1% BSA, 100 U/mL
pen-strep, 0.1 mmol/L 2-mercaptoethanol, 2 mmol/L L-glutamine, and the
following recombinant human cytokines: rh Stem cell factor (rhSCF), 50 ng/mL; rh granulocyte-monocyte colony-stimulating factor (rhGM-CSF), 10 ng/mL; and rh IL-3 (rhIL-3), 10 ng/mL. The Methocult GF H 4534 medium
was supplemented with either rhIL-5, 3 nmol/L (see Fig 4B); or PBS (A);
rhIL-5, 3 nmol/L (B); synthetic guinea pig eotaxin, 3 nmol/L (C) (see
Fig 4C). Leukocytes were plated in duplicate 35-mm tissue culture
dishes at 5 × 105 leukocytes per dish and maintained in a
humidified atmosphere at 37°C, 5% CO2. On day 14, the
number of colonies per plate (defined as aggregates of greater than 40 cells) were scored under an inverted microscope.
Eosinophil-colony-forming units (Eo-CFU) and granulocyte-monocyte colony-forming units (GM-CFU) were identified from cytospin
preparations of individual colonies (10 CFU examined per plate) after
staining with methylene blue and eosin. Assessment of progenitor cell
release in vivo was not feasible because the small volume blood samples collected for time course studies of eosinophil release did not contain
sufficient numbers of leukocytes for the colony-forming assays.
View larger version (30K):
[in this window]
[in a new window]
| Fig 3.
Eosinophil release from bone marrow induced by eotaxin.
The femoral bone marrow was perfused in situ with modified Krebs-Ringer bicarbonate buffer via the external iliac artery and 10-minute fractions were collected from the external iliac vein. (A) Kinetics of
eosinophil release after a 10-minute infusion (indicated by  ) of
eotaxin (3 nmol/L) or vehicle (PBS/0.1% BSA). Results represent the
number of eosinophils per milliliter of perfusate in each 10-minute
fraction, mean ± SEM (n = five to six perfusions). ( ), Eotaxin
3 nmol/L; ( ), Vehicle. (B) Total eosinophil release and total
release of other leukocytes induced by a 10-minute infusion of eotaxin
(0.03 and 3 nmol/L) or vehicle. Results show the total number of
eosinophils or other leukocytes released during the 80-minute perfusion
period, mean ± SEM (n = five to six perfusions). A significant
difference between eotaxin and vehicle injected group is indicated by
**(P < .01). (C) Kinetics of eosinophil release after a
30-minute infusion (indicated by ) of eotaxin (3 nmol/L) or vehicle.
Results represent the number of eosinophils per milliliter of perfusate
in each 10-minute fraction, mean ± SEM (n = four perfusions).
() Eotaxin, 3 nmol/L; (), Vehicle. (D) Eosinophil mobilization
after a 30-minute infusion of eotaxin (3 nmol/L) or vehicle. Results
(from experiment shown in C) show the total number of eosinophils
released during the 110-minute perfusion period (left y-axis) and the
number of eosinophils present in the femoral bone marrow after the
110-minute perfusion period (right y-axis), mean ± SEM (n = four
perfusions). A significant difference between eotaxin and vehicle
infused groups is indicated by *(P < .05) or
**(P < .01).
|
|
View larger version (63K):
[in this window]
[in a new window]
| Fig 1.
Transwell filter chemotaxis assay of guinea
pig bone marrow eosinophils. A suspension of 3 × 106 bone
marrow leukocytes was placed in the upper chamber, with eotaxin present
in the lower chamber ( ) or upper chamber (#). Leukocytes that
accumulated in the lower chamber were quantified using flow cytometry
(FACScan; Beckton Dickinson). (A,B) Representative FACS dot-plot light
forward scatter/side scatter profile of (A) mixed bone marrow leukocyte
population placed into the upper Transwell chamber and (B) leukocytes
migrated into the lower chamber in response to eotaxin (3 nmol/L, lower
chamber for 30 minutes. Eosinophils shown in red). (C,D) May-Grunwald
and Giemsa-stained cytospin preparations of (C) mixed bone marrow
leukocyte population placed into the upper Transwell chamber and (D)
leukocytes migrated into the lower chamber in response to eotaxin (3 nmol/L, lower chamber for 30 minutes). (E) Total eosinophils migrated
in response to eotaxin present in the lower chamber (0 to 10 nmol/L) or
upper chamber (3 nmol/L; #). Data represent the number of eosinophils migrated in 1 hour, mean ± SEM, using different cell preparations n
= 6 to 12. No significant increase in eosinophil migration was observed when eotaxin (3 nmol/L) was added to the upper chambers. A
significant difference between test and control groups is indicated by
*(P < .05) or **(P < .01). (F) Time course of
eosinophil chemotaxis induced by eotaxin (3 nmol/L, lower chamber).
Data represent the number of eosinophils migrated at each time point,
mean ± SEM for a single cell preparation performed in triplicate. The
results shown are representative of three identical experiments. (), Eotaxin 3 nmol/L; (), Vehicle.
|
|
View larger version (18K):
[in this window]
[in a new window]
| Fig 4.
Eotaxin stimulates release of colony-forming units from
femoral bone marrow. (A) Total eosinophil and total other leukocyte release from the perfused hind limb stimulated by a 10-minute infusion
of eotaxin (3 nmol/L) or vehicle (PBS/0.1% BSA), counted in an
improved Neubauer hemacytometer. Results show the total number of
eosinophils and other leukocytes released during the 60-minute
perfusion period, mean ± SEM (n = seven to eight perfusions). (B)
GM-CFU () and Eo-CFU ( ) release after a 10-minute infusion of
eotaxin (3 nmol/L) or vehicle. The colony-forming assay was performed
in Methocult GF H4534 methylcellulose-based medium supplemented with
IL-5 (3 nmol/L). Results are expressed as the number of GM-CFU or
Eo-CFU present per 5 × 105 total leukocytes released
during the 60-minute perfusion period, mean ± SEM of seven to eight
perfusions, CFU assay performed in duplicate. A significant difference
between Eo-CFU released in eotaxin and in vehicle infused groups is
indicated by ***(P < .001). (C) Colony-forming unit assay
of leukocytes released by eotaxin (3 nmol/L) performed in Methocult GF
H4534 medium supplemented with either PBS (A), IL-5 (3 nmol/L) (B), or
eotaxin (3 nmol/L) (C). Results are expressed as the number of GM-CFU
() or Eo-CFU () present per 5 × 105 total
leukocytes released during the 60-minute perfusion period, mean ± SEM
of three perfusions, CFU assay performed in duplicate. A significant
difference between the number of Eo-CFU formed in the presence of IL-5
compared with either PBS or eotaxin is indicated by
*(P < .05).
|
|
Statistical analysis.
Data is presented as mean ± standard error of the mean (SEM). All
statistical tests were performed using untransformed data. For analysis
of two groups the unpaired two-tail Student's t-test was
performed. For analysis of three or more groups one-way analysis of
variance was performed, followed by either Bonferroni's multiple comparisons posttest, or Dunnett's posttest for
comparison with a control group. A value of P < .05 was
considered statistically significant.
| |
RESULTS |
Chemotactic effect of eotaxin on bone marrow eosinophils in vitro.
The chemotactic activity of eotaxin on guinea pig bone marrow cell
suspensions was investigated in a Transwell filter assay system in
vitro. Figure 1A shows the FACS forward scatter/side scatter profile of
the mixed bone marrow leukocyte population placed into the upper
chamber of the Transwell filter. A cytospin preparation of this cell
population is shown in Fig 1C. Figure 1B shows the FACS scatter
characteristics of the leukocytes that migrated into the lower chamber
in response to eotaxin (3 nmol/L, lower chamber for 30 minutes). The
high side-scatter and low forward-scatter profile of the migrated
leukocytes (Fig 1B, shown in red) is characteristic of eosinophils.
Cytospin preparations of these leukocytes (Fig 1D) showed cells with a
bilobed nucleus that stained intensely with May-Grunwald's stain,
indicating that these cells were eosinophils.
Figures 1E and F illustrate that basal migration of eosinophils was
low, and that a positive gradient of eotaxin stimulated dose-related
migration of eosinophils, which reached a maximum at 30 minutes. The
effect of eotaxin was selective for eosinophils: there was no increase
in the migration of other leukocyte types.
Effect of IV eotaxin.
To investigate if chemotaxis across the bone marrow sinus endothelium
would induce a blood eosinophilia in vivo, eotaxin (1 nmol/kg) was
injected IV into guinea pigs and the numbers of circulating eosinophils
monitored over a 2-hour time period. At the end of the experiment the
number of eosinophils present in the femoral bone marrow was
determined. As shown in Fig 2A,
circulating eosinophil levels rose rapidly after the IV eotaxin
injection, when compared with PBS-injected controls. Circulating
eosinophil numbers were significantly elevated at 15 minutes after
eotaxin injection. Maximal levels were attained at 20 to 30 minutes. A
significant decrease in eosinophils retained in the femoral bone marrow
was observed in the eotaxin-injected group when measured at 2 hours (Fig 2B).
View larger version (14K):
[in this window]
[in a new window]
| Fig 2.
The effect of IV eotaxin on blood and bone
marrow eosinophil numbers. After injection of eotaxin, circulating
eosinophil numbers were determined at multiple time points over a
2-hour period. Femoral marrow eosinophil numbers were determined after
2 hours. (A) Kinetics of blood eosinophilia induced by eotaxin (1 nmol/kg). Results show the number of eosinophils per milliliter of
blood at each time point, mean ± SEM (n = 4 animals). Eotaxin
stimulated a significant *(P < .05) or
**(P < .01) blood eosinophilia after 15 minutes compared
with the vehicle-injected group. (), Eotaxin 1 nmol/kg; (),
Vehicle. (B) Femoral marrow eosinophil numbers. Results show the total
number of morphologically mature eosinophils in femoral bone marrow in
one femur 2 hours after injection of eotaxin (1 nmol/kg) or vehicle,
mean ± SEM, (n = 4 animals). A significant difference between
eotaxin- and vehicle-injected groups is shown by
*(P < .05).
|
|
Effect of eotaxin on eosinophil release from bone marrow perfused in
situ.
To show directly that eotaxin stimulates release of eosinophils from
the bone marrow, we set up a perfusion system of the femur. The femoral
bone marrow was perfused in situ with modified Krebs-Ringer bicarbonate
buffer via the external iliac artery and 10-minute fractions were
collected from the external iliac vein. Transmission electron
microscopy of the perfused bone marrow confirmed that the marrow
cytoarchitecture remained intact during this procedure (data not
shown). When perfused with buffer alone, approximately 5 × 106 leukocytes were released into the perfusate over an
80-minute period, of which 0.25 × 106 (5% of total) were
eosinophils and the remainder were neutrophils (85%) and mononuclear
cells (10%). A 10-minute pulse of eotaxin at 3 nmol/L induced a rapid,
transient release of eosinophils into the perfusate, which peaked 10 minutes after the start of the infusion (Fig
3A) with no effect on other cell types
(Fig 3B). Approximately 1.5 × 106 eosinophils were
released in total (Fig 3B).
When the infusion of eotaxin was extended from 10 to 30 minutes, the
release of eosinophils was considerably prolonged (Fig 3C). As with the
10-minute infusion, release rapidly declined when the infusion was
terminated. The release of eosinophils corresponded to a reduction in
eosinophils retained in the bone marrow at the end of the perfusion
period (30-minute eotaxin infusion; Fig 3D).
Effect of eotaxin on hematopoietic progenitor release from bone
marrow perfused in situ.
Perfusion of the femoral bone marrow in situ with eotaxin was performed
to determine whether eotaxin stimulated the release of colony-forming
cells directly from the bone marrow. A 10-minute pulse of either
vehicle or 3 nmol/L eotaxin was infused into the bone marrow. Leukocyte
release was similar to that described above: a total of 1.24 ± 0.2 × 106 eosinophils and 4.31 ± 0.5 × 106
other leukocytes were released after infusion of eotaxin as compared with 0.2 ± 0.1 × 106 eosinophils and 4.3 ± 0.5 × 106 other leukocytes released when vehicle was infused (Fig
4A). This system was suitable for
obtaining sufficient numbers of leukocytes for culture, uncontaminated
by cells which interfere with the growth of progenitors in semisolid
cultures. Leukocytes released were plated in methylcellulose-based
medium containing a cytokine profile optimised to detect Eo-CFU and
GM-CFU.34 After a 14-day incubation period the number of
colonies (aggregates of greater than 40 cells) were counted. There was
a significant increase in the total number of colonies formed from
leukocytes released in response to eotaxin as compared with vehicle,
this increase being accounted for by a significant increase in Eo-CFU
with no significant difference in the number of GM-CFU (Fig 4B). Of the total colonies formed, from progenitors mobilized by eotaxin, 59% were
identified as Eo-CFU, whereas only 17% of the colonies formed from the
vehicle-infused group were Eo-CFU.
In three of these experiments the IL-5 in the methylcellulose medium
was replaced by either PBS vehicle or eotaxin (Fig 4C). Leukocytes
released by eotaxin infusion were therefore cultured for 14 days in the
presence of rhSCF, GM-CSF, and IL-3 together with either PBS (A), IL-5
(B), or eotaxin (C). The results show that the total number of colonies
formed was not affected by the presence of either IL-5 or eotaxin in
the medium. Of the total colonies, 15% were identified as eosinophil
colonies when the medium contained PBS. Addition of eotaxin (3 nmol/L)
to the medium had no effect on the percentage of eosinophil colonies
formed. In contrast, IL-5 increased the percentage of eosinophil
colonies significantly to 55%.
These results show that eotaxin stimulates a direct mobilization of
colony-forming progenitors from the bone marrow. Differentiation of
these colony-forming cells into eosinophils is dependent on the
presence of IL-5. To determine whether IL-5 could mobilize colony-forming progenitors from the bone marrow, IL-5 (0.8 nmol/L) was
infused for 60 minutes into the bone marrow. The total number of
eosinophils and other leukocytes released
(0.8 ± 0.3 × 106 and
4.0 ± 0.5 × 106, respectively) were not
significantly different from the release observed with a 10-minute
infusion of eotaxin (3 nmol/L; Fig 4A). In colony assays performed
exactly as described above, there was no significant increase in the
number of colonies formed from leukocytes released in response to IL-5
(Eo-CFU 0.7 ± 0.3 and GM-CFU 7.0 ± 0.5/5 × 105
leukocytes plated) as compared with vehicle (Fig 4B). Thus, under these
conditions IL-5 did not stimulate the mobilization of eosinophil progenitors from the bone marrow.
To determine whether eosinophil progenitors could be detected in the
circulation, blood was collected 30 minutes after IV injection of
Guinea pigs with either vehicle or eotaxin 1 nmol/kg. This time point
was chosen because it corresponded to the maximal eosinophil release
(Fig 2A). The blood was lysed to remove red blood cells and the
leukocytes (2 × 105) were plated in methocult medium
supplemented with rhSCF, GM-CSF, IL-3, and IL-5. After a 14-day
incubation period we did not detect any colonies in either the vehicle-
or eotaxin-injected group. This result may reflect the fact that
eosinophil progenitors, once released, are rapidly redistributed in
vivo, either a result of homing back to the bone marrow or of
recruitment into extravascular sites, such as the lung, where we know
eotaxin is generated constitutively.16
Potentiating effect of IL-5 on eotaxin-induced chemotaxis of bone
marrow eosinophils in vitro.
Using the in vitro chemotaxis, assay a detailed dose-response curve of
bone marrow eosinophil migration induced by eotaxin was performed.
Significant migration was observed at eotaxin concentrations of 1 nmol/L and above (Fig 5A). Preincubation of
bone marrow leukocytes with IL-5 (3 nmol/L for 15 minutes at 37°C)
induced a small, selective migration of bone marrow eosinophils when
subsequently tested in the Transwell system (Fig 5B). The effect was
associated with chemokinesis because the same magnitude of migration
occurred when IL-5 was added to the upper chamber alone, the lower
chamber alone, or both the lower and upper chamber (results not shown). This was in contrast to the chemotactic effect of eotaxin, where migration was not observed with the chemokine in the upper chamber (Fig
1E).
View larger version (13K):
[in this window]
[in a new window]
| Fig 5.
The effect of IL-5 on eotaxin-stimulated chemotaxis of
guinea pig bone marrow eosinophils. Bone marrow leukocytes were
preincubated with IL-5 (3 nmol/L) or vehicle for 15 minutes at 37°C.
(A) The effect of IL-5 (3 nmol/L, upper chamber) on bone marrow
eosinophil chemotaxis induced by eotaxin (0 to 30 nmol/L, lower
chamber). Data represent the number of eosinophils migrated after 1 hour, mean ± SEM of a single cell preparation performed in
triplicate. (), IL-5 3 nmol/L; (), Vehicle. (B) The effect of
IL-5 (3 nmol/L) and eotaxin (0.3 nmol/L) alone or in combination on the
chemotaxis of bone marrow eosinophils (results from experiment shown in
Fig 5A). Results represent the number of eosinophils migrated after 1 hour, mean ± SEM of a single cell preparation performed in
triplicate. The results shown are representative of three identical
experiments. Significant difference between IL-5 alone and vehicle
indicated by  (P < .05), or between eotaxin together with
IL-5 and IL-5 alone by *(P < .05).
|
|
IL-5 was able to prime bone marrow eosinophils to enhance migration in
response to eotaxin. Preincubation of bone marrow cell suspensions with
IL-5 (3 nmol/L for 15 minutes at 37°C) considerably enhanced the
migration of eosinophils stimulated by eotaxin in the lower chamber
(Fig 5A and B). Synergism was striking at an eotaxin concentration of
0.3 nmol/L, which did not induce significant migration when tested on
unprimed cells (Fig 5B).
Effects of IL-5/eotaxin combinations on eosinophil release from
perfused bone marrow.
The experiments shown in Fig 5 showed synergism between IL-5 and
eotaxin to induce chemotaxis of bone marrow eosinophils in vitro.
Experiments were designed to investigate if such synergism was also
demonstrable in bone marrow eosinophil release using the in situ
perfusion system.
Perfusion of the femoral bone marrow was performed for a total of 110 minutes. After 20 minutes, IL-5 (0.3 nmol/L) or vehicle was infused for
10 minutes. A second infusion of a low dose of eotaxin (0.3 nmol/L) or
PBS infusion was performed at 50 to 60 minutes. The results of the
first and second infusions are shown in Fig
6. Infusions of vehicle/eotaxin induced no
significant eosinophil release compared with vehicle/vehicle infusions.
IL-5/vehicle infusions induced eosinophil release; however, the
kinetics were delayed in onset and of a protracted time course (Fig 6A)
when compared with the rapid onset and transient release produced by higher concentrations of eotaxin (Fig 4). A 10-minute pulse of eotaxin
(0.3 nmol/L) administered after a first 10-minute pulse of IL-5
produced a rapid and dramatically enhanced eosinophil release (Fig 6A
and B). None of these combinations had any effect on the release of
other cell types (Fig 6B).
View larger version (21K):
[in this window]
[in a new window]
| Fig 6.
Eotaxin (EOT) and IL-5 act synergistically to release
eosinophils from bone marrow. Perfusion of the femoral bone marrow was performed for a total of 110 minutes. (A) Kinetics of eosinophil release induced by a 10-minute infusion (indicated by 1) of IL-5
(0.3 nmol/L) or vehicle (PBS/0.1% BSA) followed 20 minutes later by a
10-minute infusion (indicated by 2) of eotaxin (0.3 nmol/L) or
vehicle. Results represent the number of eosinophils per milliliter of
perfusate in each 10-minute fraction, mean ± SEM (n = five to
eight perfusions). A significant difference between IL-5 plus eotaxin
and IL-5 alone at equivalent time point represented by
**(P < .01) or ***(P < .001). (B) Total
eosinophil release and total release of other leukocytes induced by a
10-minute infusion of IL-5 (0.3 nmol/L) or vehicle followed 20 minutes
later by a 10-minute infusion of eotaxin (0.3 nmol/L) or vehicle.
Results show the total number of eosinophils or other leukocytes
released during the 110-minute perfusion period, mean ± SEM
(n = five to eight perfusions). A significant difference between
IL-5 alone and vehicle is indicated by (P < .05) and a
significant difference between IL-5 plus eotaxin and IL-5 alone by
**(P < .01).
|
|
| |
DISCUSSION |
The classical experiments of Samter et al35 showed that
guinea pig lung produced a factor during anaphylactic shock that induced a blood eosinophilia. These investigators deduced that an
"eosinotactic substance" was produced in the lung and that the
same substance induced both local eosinophil recruitment in the lung
and release of mature eosinophils from the bone marrow into the blood.
In contrast, our recent results suggested that these two activities are
mediated by separate chemical signals: eotaxin mediating local
eosinophil recruitment5 and IL-5 facilitating release of
cells from the bone marrow.15,36 Although IL-5 is clearly
important in releasing bone marrow eosinophils during an allergic
reaction in the lung,16,37 the results presented here show
that Samter et al35 were essentially correct in deducing that the same chemoattractant can mediate both local eosinophil recruitment and their release from the bone marrow.
Previous studies have shown that eotaxin is a potent chemoattractant
that promotes circulating eosinophils to adhere to and emigrate through
a microvessel wall into the extravascular space at sites of
inflammation.4,5,11,12,14,15 We evaluated whether this
chemoattractant activity could induce migration of eosinophils into the
bone marrow sinuses. When tested in a chemotaxis assay in vitro,
eotaxin was found to induce a selective chemotaxis of eosinophils from
a bone marrow mixed cell suspension (Fig 1). In vivo, IV eotaxin
induced a rapid onset and sustained blood eosinophilia, which
correlated with a loss of eosinophils from the bone marrow (Fig 2).
When infused into the arterial supply of the perfused femoral bone
marrow in situ, eotaxin induced a rapid release of eosinophils into the
draining vein, correlating with a reduction in retained cells (Fig 3).
Release was sustained during the eotaxin infusion, but rapidly declined
thereafter. The cells released by eotaxin were not tachyphylactic to
the chemokine, as these cells responded to eotaxin when subsequently
tested in the chemotaxis assay in vitro (data not shown).
One difference reported in mice with targeted disruption of the eotaxin
gene as compared with wild-type mice was a reduction in circulating
eosinophil levels despite apparently normal
hematopoiesis.38 This finding is consistent with the
results presented in this paper. Mould et al39 showed that
IV eotaxin stimulated a rapid blood eosinophilia in mice, but in
contrast to our results, did not detect a decrease in bone marrow
eosinophil numbers. In contrast to the substantial reserve of
eosinophils in guinea pig40 and human bone
marrow,32 the mouse has only a small number of these cells.41 However, the reserve is increased after
sensitization.41
It has previously been reported that the chemokines IL-8 and
MIP-1 stimulate the mobilization of hematopoietic
progenitor cells from the bone marrow.29-31 Therefore, we
have assessed whether eotaxin stimulates the release of hematopoietic
progenitors from the guinea pig bone marrow using a
methylcellulose-based clonogenic assay. We observed that a 10-minute
infusion of 3 nmol/L eotaxin in the femoral bone marrow in situ
perfusion system stimulated a significant increase in the release of
colony-forming progenitors over basal levels. IL-5 stimulates the
mobilization of mature eosinophils from the bone marrow15
(Fig 6). However, in this study we did not detect a significant
increase in the release of colony-forming progenitor cells in response
to IL-5. An increase in eosinophil progenitor cells has been reported
in the blood of atopics,25 in asthmatics during
exacerbation,26,27 and in nasal polyp tissue.28
From the results presented here it seems that colony-forming
progenitors express the eotaxin receptor CCR3, and can be mobilized
from the bone marrow into the blood by eotaxin. Factors that regulate
the subsequent local recruitment of these progenitors into tissues,
such as nasal polyp, have not been identified. Eotaxin, which has been
detected in human asthmatic lung and nasal polyps10,11,13
is a potential candidate for this function. Previously, cytokines have
been identified that control colony formation and
differentiation.42 In particular, IL-5 is known to be a
late differentiation factor for eosinophils.43,44 In this
study colony-forming progenitors released in response to eotaxin were
cultured in the presence of SCF, IL-3, and GM-CSF together with either
PBS, IL-5, or eotaxin. We show that the differentiation of these
progenitors into eosinophils was dependent on the presence of IL-5. In
contrast, eotaxin, at the same concentration as IL-5, did not induce
differentiation of these colonies into eosinophils in these
experiments. Therefore, it is possible that IL-545,46 together with other cytokines, such as GM-CSF47 and
IL-3,48 generated at sites of allergic inflammation, may act locally to support colony formation and differentiation. This hypothesis predicts another example of the cooperative effects of IL-5
and eotaxin.
The detailed mechanisms involved in the mobilization of leukocytes from
the bone marrow remain to be established.17 The results
presented here suggest that the development of a chemoattractant gradient across the bone marrow sinus endothelium induces eosinophil release. This has parallels with neutrophil release because the IV
injection of neutrophil chemoattractants has been shown to induce a
transient blood neutropenia followed by a leukocytosis, the latter
suggested to involve bone marrow release.18,30,31 In the
perfusion system the effect of eotaxin was rapid in onset and transient
(Fig 3). This suggests that the migration through the endothelium
ceases as the gradient disappears. In contrast, IL-5 induced a
sustained release of eosinophils that was delayed in onset (Fig 6).
This difference in kinetics may be related to a difference in
mechanisms of action. We found in the in vitro Transwell system that
eotaxin induces chemotaxis of bone marrow eosinophils, whereas IL-5
induces chemokinesis (Fig 5 and Rankin et al unpublished,
1997). Consistent with these findings, a chemokinetic effect of IL-5 on
human peripheral eosinophils has been reported.19 A
combination of these effects would seem to be very efficient in
mobilizing eosinophils into bone marrow sinuses, ie, eosinophil chemokinesis stimulated by IL-5 and chemotaxis stimulated by a gradient
of eotaxin across the sinus endothelium. Accordingly, we found marked
synergism between eotaxin and IL-5 in both the Transwell chemotaxis
assay system in vitro (Fig 5) and the in situ perfusion system (Fig 6).
This was most striking with low doses of eotaxin, which produced
insignificant effects on eosinophil migration or release when tested
alone.
Neutralization of IL-5 using TRFK5 antibody has been
shown to suppress the release of eosinophils from the bone marrow and the resultant blood eosinophilia induced by allergen challenge of
guinea pig lung in vivo.16,37 The antibody had no effect on
eotaxin generation in these experiments.16 These results could be accounted for by a synergistic interaction between endogenous eotaxin and IL-5 on bone marrow eosinophil release, as we have observed. Furthermore, mice with targeted disruption of the IL-5 gene
have a significant, although reduced, level of blood and bone marrow
eosinophils.49 Thus, other mediators seem to be able to
compensate for the loss of IL-5.
Measurements of eotaxin levels in sensitized guinea pig lung tissue
have shown a rapid clearance of the chemokine between 6 and 12 hours
after allergen challenge.16 Some of this clearance is
likely to be into the local microvasculature. The duffy antigen receptor for chemokines on red blood cells, acting as a chemokine sink,
may prevent high levels of circulating, unbound
chemokine.50 However, plasma levels of eotaxin,
particularly during active phases of inflammation, may be sufficient to
exert an important role in regulating blood eosinophil levels, probably
in cooperation with IL-5.
These results suggest that the process of bone marrow eosinophil
release and tissue eosinophil recruitment share a common feature, fast
cell migration across a vascular endothelium, albeit in opposite
directions. Furthermore, the data show a dramatic cooperation between
chemotaxis and chemokinesis using agents selectively exhibiting these
activities.
| |
FOOTNOTES |
Submitted November 17, 1997;
accepted December 30, 1997.
Supported by the Wellcome Trust and the National Asthma Campaign,
London, UK.
Address reprint requests to Sara Rankin, PhD, Leukocyte
Biology Section, Biomedical Sciences Division, Imperial College School of Medicine at the National Heart and Lung Institute, London SW3 6LY,
UK.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be here-by marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
REFERENCES |
1.
de Monchy JGR,
Kauffman HF,
Venge P,
Koeter GH,
Jansen HM,
Sluiter HJ,
de Vries K:
Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions.
Am Rev Respir Dis
131:373,
1985[Medline]
[Order article via Infotrieve]
2.
Bousquet J,
Chanez P,
Lacoste JY,
Barneon G,
Ghavanian MN,
Enander I,
Venge P,
Ahlstedt S,
Simony-Lafontaine J,
Godard P,
Michel P:
Eosinophilic inflammation in asthma.
N Engl J Med
323:1033,
1990[Abstract]
3.
Bradley BL,
Azzawi M,
Jacobson M,
Assoufi B,
Collins JV,
Irani AA,
Schwartz LB,
Durham SR,
Jeffery PK,
Kay AB:
Eosinophils, T-lymphocytes, mast cells, neutrophils, and macrophages in bronchial biopsy specimens from atopic subjects with asthma: Comparison with biopsy specimens from atopic subjects without asthma and normal control subjects and relationship to bronchial hyperresponsiveness.
J Allergy Clin Immunol
88:661,
1991[Medline]
[Order article via Infotrieve]
4.
Griffiths-Johnson DA,
Collins PD,
Rossi AG,
Jose PJ,
Williams TJ:
The chemokine, Eotaxin, activates guinea-pig eosinophils in vitro, and causes their accumulation into the lung in vivo.
Biochem Biophys Res Commun
197:1167,
1993[Medline]
[Order article via Infotrieve]
5.
Jose PJ,
Griffiths-Johnson DA,
Collins PD,
Walsh DT,
Moqbel R,
Totty NF,
Truong O,
Hsuan JJ,
Williams TJ:
Eotaxin: A potent eosinophil chemoattractant cytokine detected in a guinea-pig model of allergic airways inflammation.
J Exp Med
179:881,
1994[Abstract/Free Full Text]
6.
Jose PJ,
Adcock IM,
Griffiths-Johnson DA,
Berkman N,
Wells TNC,
Williams TJ,
Power CA:
Eotaxin: Cloning of an eosinophil chemoattractant cytokine and increased mRNA expression in allergen-challenged guinea-pig lungs.
Biochem Biophys Res Commun
205:788,
1994[Medline]
[Order article via Infotrieve]
7.
Rothenberg ME,
Luster AD,
Lilly CM,
Drazen JM,
Leder P:
Constitutive and allergen-induced expression of eotaxin mRNA in the guinea pig lung.
J Exp Med
181:1211,
1995[Abstract/Free Full Text]
8.
Rothenberg ME,
Luster AD,
Leder P:
Murine eotaxin: An eosinophil chemoattractant inducible in endothelial cells and in interleukin 4-induced tumor suppression.
Proc Natl Acad Sci USA
92:8960,
1995[Abstract/Free Full Text]
9.
Gonzalo J,
Jia G,
Aguirre V,
Friend D,
Coyle AJ,
Jenkins NA,
Lin G,
Katz H,
Lichtman A,
Copeland N,
Kopf M,
Gutierrez-Ramos J:
Mouse eotaxin expression parallels eosinophil accumulation during lung allergic inflammation but it is not restricted to a Th2-type response.
Immunity
4:1,
1996[Medline]
[Order article via Infotrieve]
10.
Ponath PD,
Qin S,
Ringler DJ,
Clark-Lewis I,
Wang J,
Kassam N,
Smith H,
Shi X,
Gonzalo J,
Newman W,
Gutierrez-Ramos J,
Mackay CR:
Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding and functional properties suggest a mechanism for the selective recruitment of eosinophils.
J Clin Invest
97:604,
1996[Medline]
[Order article via Infotrieve]
11.
Garcia-Zepeda EA,
Rothenberg ME,
Ownbey RT,
Celestin J,
Leder P,
Luster AD:
Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia.
Nat Med
2:449,
1996[Medline]
[Order article via Infotrieve]
12.
Rothenberg ME,
Ownby R,
Mehlhop PD,
Loiselle PM,
Van de Rijn M,
Bonventre JV,
Oettgen HC,
Leder P,
Luster AD:
Eotaxin triggers eosinophil-selective chemotaxis and calcium flux via distinct receptor and induces pulmonary eosinophilia in the presence of interleukin 5 in mice.
Mol Med
2:334,
1996[Medline]
[Order article via Infotrieve]
13.
Mattoli S,
Stacey MA,
Sun G,
Bellini A,
Marini M:
Eotaxin expression and eosinophilic inflammation in asthma.
Biochem Biophys Res Commun
236:299,
1997[Medline]
[Order article via Infotrieve]
14.
Lamkhioued B,
Renzi PM,
Younes A,
Garcia-Zepeda EA,
Allakhverdi Z,
Ghaffar O,
Rothenberg MD,
Luster AD,
Hamid QA:
Increased expression of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation.
J Immunol
159:4593,
1997[Abstract]
15.
Collins PD,
Marleau S,
Griffiths-Johnson DA,
Jose PJ,
Williams TJ:
Co-operation between interleukin-5 and the chemokine, eotaxin, to induce eosinophil accumulation in vivo.
J Exp Med
182:1169,
1995[Abstract/Free Full Text]
16.
Humbles AA,
Conroy DM,
Marleau S,
Rankin SM,
Palframan RT,
Proudfoot AEI,
Wells TNC,
Dechun L,
Jeffery PK,
Griffiths-Johnson DA,
Williams TJ,
Jose PJ:
Kinetics of eotaxin generation and its relationship to eosinophil accumulation in allergic airways disease: Analysis in a guinea pig model in vivo.
J Exp Med
186:601,
1997[Abstract/Free Full Text]
17.
Petrides PE,
Dittmann KH:
How do normal and leukemic white blood cells egress from the bone marrow? Morphological facts and biochemical riddles.
Blut
61:3,
1990[Medline]
[Order article via Infotrieve]
18.
Jagels MA,
Hugli TE:
Neutrophil chemotactic factors promote leukocytosis. A common mechanism for cellular recruitment from bone marrow.
J Immunol
148:1119,
1992[Abstract]
19.
Schweizer RC,
van Kessel-Welmers BAC,
Warringa RAJ,
Maikoe T,
Raaijmakers JAM,
Lammers JJ,
Koenderman L:
Mechanisms involved in eosinophil migration. Platelet-activating factor-induced chemotaxis and interleukin-5-induced chemokinesis are mediated by different signals.
J Leukoc Biol
59:347,
1996[Abstract]
20.
Okada S,
Kita H,
George TJ,
Gleich GJ,
Leiferman KM:
Transmigration of eosinophils through basement membrane components in vitro: Synergistic effects of platelet-activating factor and eosinophil-active cytokines.
Am J Respir Cell Mol Biol
16:455,
1997[Abstract]
21.
Wang JM,
Rambaldi A,
Biondi A,
Chen ZG,
Sanderson CJ,
Mantovani A:
Recombinant human interleukin 5 is a selective eosinophil chemoattractant.
Eur J Immunol
19:701,
1989[Medline]
[Order article via Infotrieve]
22.
Sehmi R,
Wardlaw AJ,
Cromwell O,
Kurihara K,
Waltmann P,
Kay AB:
Interleukin-5 selectively enhances the chemotactic response of eosinophils obtained from normal but not eosinophilic subjects.
Blood
79:2952,
1992[Abstract/Free Full Text]
23.
Yamaguchi Y,
Hayashi Y,
Sugama Y,
Miura Y,
Kasahara T,
Kitamura S,
Torisu M,
Mita S,
Tominaga A,
Takatsu K,
Suda T:
Highly purified murine interleukin 5 (IL-5) stimulates eosinophil function and prolongs in vitro survival. IL-5 as an eosinophil chemotactic factor.
J Exp Med
167:1737,
1988[Abstract/Free Full Text]
24. Hakansson L, Venge P: Priming of eosinophil and neutrophil
migratory responses by interleukin 3 and interleukin 5. APMIS 102:308,
1994
25.
Sehmi R,
Howie K,
Sutherland DR,
Schragge W,
O'Byrne PM,
Denburg JA:
Increased levels of CD34+ hemopoietic progenitor cells in atopic subjects.
Am J Respir Cell Mol Biol
15:645,
1996[Abstract]
26.
Gibson PG,
Dolovich J,
Girgis-Gabardo A,
Morris MM,
Anderson M,
Hargreave FE,
Denburg JA:
The inflammatory response in asthma exacerbation: Changes in circulating eosinophils, basophils and their progenitors.
Clin Exp Allergy
20:661,
1990[Medline]
[Order article via Infotrieve]
27.
Gibson PG,
Manning PJ,
O'Byrne PM,
Girgis-Gabardo A,
Dolovich J,
Denburg JA,
Hargreave FE:
Allergen-induced asthmatic responses. Relationship between increases in airway responsiveness and increases in circulating eosinophils, basophils, and their progenitors.
Am Rev Respir Dis
143:331,
1991[Medline]
[Order article via Infotrieve]
28.
Otsuka H,
Dolovich J,
Richardson M,
Bienenstock J,
Denburg JA:
Metachromatic cell progenitors and specific growth and differentiation factors in human nasal mucosa and polyps.
Am Rev Respir Dis
136:710,
1987[Medline]
[Order article via Infotrieve]
29.
Lord BI,
Woolford LB,
Wood LM,
Czaplewski LG,
McCourt M,
Hunter MG,
Edwards RM:
Mobilization of early hematopoietic progenitor cells with BB-10010: A genetically engineered variant of human macrophage inflammatory protein-a.
Blood
85:3412,
1995[Abstract/Free Full Text]
30.
Laterveer L,
Lindley IJ,
Hamilton MS,
Willemze R,
Fibbe WE:
Interleukin-8 induces rapid mobilization of hematopoietic stem cells with radioprotective capacity and long-term myelolymphoid repopulating ability.
Blood
85:2269,
1995[Abstract/Free Full Text]
31.
Laterveer L,
Lindley IJ,
Heemskerk DP,
Camps JA,
Pauwels EK,
Willemze R,
Fibbe WE:
Rapid mobilization of hematopoietic progenitor cells in rhesus monkeys by a single intravenous injection of interleukin-8.
Blood
87:781,
1996[Abstract/Free Full Text]
32. Spry CJF: Eosinophils. A Comprehensive Review, and Guide to the
Scientific and Medical Literature. New York, NY, Oxford University
Press, 1988
33.
Kimura I,
Moritani Y,
Tanizaki Y:
Basophils in bronchial asthma with reference to reagin-type allergy.
Clin Allergy
3:195,
1973[Medline]
[Order article via Infotrieve]
34.
Shalit M,
Sekhsaria S,
Malech HL:
Modulation of growth and differentiation of eosinophils from human peripheral blood CD34+ cells by IL5 and other growth factors.
Cell Immunol
160:50,
1995[Medline]
[Order article via Infotrieve]
35.
Samter M,
Kofoed MA,
Pieper W:
A factor in lungs of anaphylactically shocked guinea pigs which can induce eosinophilia in normal animals.
Blood
8:1078,
1953[Abstract/Free Full Text]
36.
Portanova JP,
Christine LJ,
Rangwala SH,
Compton RP,
Hirsch JL,
Smith WG,
Monahan JB:
Rapid and selective induction of blood eosinophilia by human recombinant IL-5.
Cytokine
7:775,
1995[Medline]
[Order article via Infotrieve]
37.
Kung TT,
Stelts DM,
Zurcher JA,
Adams III GK,
Egan RW,
Kreutner W,
Watnick AS,
Jones H,
Chapman RW:
Involvement of IL-5 in a murine model of allergic pulmonary inflammation: Prophylactic and therapeutic effect of an anti-IL-5 antibody.
Am J Respir Cell Mol Biol
13:360,
1995[Abstract]
38.
Rothenberg ME,
MacLean JA,
Pearlman E,
Luster AD,
Leder P:
Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia.
J Exp Med
18:1,
1997
39.
Mould AW,
Matthaei KI,
Young IG,
Foster PS:
Relationship between interleukin-5 and eotaxin in regulating blood and tissue eosinophilia in mice.
J Clin Invest
5:1064,
1997
40.
Hudson G:
The marrow reserve of eosinophils. Effect of cortical hormones on the foreign protein response.
Br J Haematol
10:122,
1964
41.
Elsas MICG,
Joseph D,
Elsas PX,
Vargafting BB:
Rapid increase in bone-marrow eosinophil production and responses to eosinopoietic interleukins triggered by intranasal allergen challenge.
Am J Respir Cell Mol Biol
17:404,
1997[Abstract/Free Full Text]
42.
Ogawa M:
Differentiation and proliferation of hematopoietic stem-cells.
Blood
81:2844,
1993[Abstract/Free Full Text]
43.
Clutterbuck EJ,
Hirst EM,
Sanderson CJ:
Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: Comparison and interaction with IL-1, IL-3, IL-6 and GM-CSF.
Blood
73:1504,
1989[Abstract/Free Full Text]
44.
Sanderson CJ:
Interleukin-5, eosinophils, and disease.
Blood
79:3101,
1992[Free Full Text]
45.
Hamid Q,
Azzawi M,
Ying S,
Moqbel R,
Wardlaw AJ,
Corrigan CJ,
Bradley B,
Durham SR,
Collins JV,
Jeffery PK,
Quint DJ,
Kay AB:
Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma.
J Clin Invest
87:1541,
1991
46.
Broide DH,
Lotz M,
Cuomo AJ,
Coburn DA,
Federman EC,
Wasserman SI:
Cytokines in symptomatic asthma airways.
J Allergy Clin Immunol
89:958,
1992[Medline]
[Order article via Infotrieve]
47.
Kato M,
Liu MC,
Stealey BA,
Friedman B,
Lichtenstein LM,
Permutt S,
Schleimer RP:
Production of granulocyte/macrophage colony-stimulating factor in human airways during allergen-induced late-phase reactions in atopic subjects.
Lymphokine Cytokine Res
11:287,
1992[Medline]
[Order article via Infotrieve]
48.
Kay AB,
Ying S,
Varney V,
Gaga M,
Durham SR,
Moqbel R,
Wardlaw AJ,
Hamid Q:
Messenger RNA expression of the cytokine gene cluster, interleukin 3 (IL-3), IL-4, IL-5, and granulocyte/macrophage colony-stimulating factor, in allergen-induced late-phase cutaneous reactions in atopic subjects.
J Exp Med
173:775,
1991[Abstract/Free Full Text]
49.
Kopf M,
Brombacher F,
Hodgkin PD,
Ramsay AJ,
Milbourne EA,
Dai WJ,
Ovington KS,
Behm CA,
Kohler G,
Young IG,
Matthaei KI:
IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses.
Immunity
4:15,
1996[Medline]
[Order article via Infotrieve]
50.
Hadley TJ,
Peiper SC:
From malaria to chemokine receptor: The emerging physiologic role of the duffy blood group antigen.
Blood
89:3077,
1997[Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. Gouwy, S. Struyf, H. Verbeke, W. Put, P. Proost, G. Opdenakker, and J. Van Damme
CC chemokine ligand-2 synergizes with the nonchemokine G protein-coupled receptor ligand fMLP in monocyte chemotaxis, and it cooperates with the TLR ligand LPS via induction of CXCL8
J. Leukoc. Biol.,
September 1, 2009;
86(3):
671 - 680.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Kovacs-Nolan, J. W. Mapletoft, Z. Lawman, L. A. Babiuk, and S. van Drunen Littel-van den Hurk
Formulation of bovine respiratory syncytial virus fusion protein with CpG oligodeoxynucleotide, cationic host defence peptide and polyphosphazene enhances humoral and cellular responses and induces a protective type 1 immune response in mice
J. Gen. Virol.,
August 1, 2009;
90(8):
1892 - 1905.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. P. Martin, S. Rankin, S. Pitchford, I. F. Charo, G. C. Furtado, and S. A. Lira
Increased Expression of CCL2 in Insulin-Producing Cells of Transgenic Mice Promotes Mobilization of Myeloid Cells From the Bone Marrow, Marked Insulitis, and Diabetes
Diabetes,
November 1, 2008;
57(11):
3025 - 3033.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Forssmann, C. Stoetzer, M. Stephan, C. Kruschinski, T. Skripuletz, J. Schade, A. Schmiedl, R. Pabst, L. Wagner, T. Hoffmann, et al.
Inhibition of CD26/Dipeptidyl Peptidase IV Enhances CCL11/Eotaxin-Mediated Recruitment of Eosinophils In Vivo
J. Immunol.,
July 15, 2008;
181(2):
1120 - 1127.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Wengner, S. C. Pitchford, R. C. Furze, and S. M. Rankin
The coordinated action of G-CSF and ELR + CXC chemokines in neutrophil mobilization during acute inflammation
Blood,
January 1, 2008;
111(1):
42 - 49.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Kang, D. H. Lee, H. Seo, J. S. Park, K. H. Nam, S. Y. Shin, C.-S. Park, and I. Y. Chung
Regulation of Functional Phenotypes of Cord Blood Derived Eosinophils by {gamma}-Secretase Inhibitor
Am. J. Respir. Cell Mol. Biol.,
November 1, 2007;
37(5):
571 - 577.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Schratl, J. F. Royer, E. Kostenis, T. Ulven, E. M. Sturm, M. Waldhoer, G. Hoefler, R. Schuligoi, I. Th. Lippe, B. A. Peskar, et al.
The Role of the Prostaglandin D2 Receptor, DP, in Eosinophil Trafficking
J. Immunol.,
October 1, 2007;
179(7):
4792 - 4799.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Farahi, A. S. Cowburn, P. D. Upton, J. Deighton, A. Sobolewski, E. Gherardi, N. W. Morrell, and E. R. Chilvers
Eotaxin-1/CC Chemokine Ligand 11: A Novel Eosinophil Survival Factor Secreted by Human Pulmonary Artery Endothelial Cells
J. Immunol.,
July 15, 2007;
179(2):
1264 - 1273.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Voehringer, N. van Rooijen, and R. M. Locksley
Eosinophils develop in distinct stages and are recruited to peripheral sites by alternatively activated macrophages
J. Leukoc. Biol.,
June 1, 2007;
81(6):
1434 - 1444.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. J. Robays, T. Maes, S. Lebecque, S. A. Lira, W. A. Kuziel, G. G. Brusselle, G. F. Joos, and K. V. Vermaelen
Chemokine Receptor CCR2 but Not CCR5 or CCR6 Mediates the Increase in Pulmonary Dendritic Cells during Allergic Airway Inflammation
J. Immunol.,
April 15, 2007;
178(8):
5305 - 5311.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Simson, J. I. Ellyard, L. A. Dent, K. I. Matthaei, M. E. Rothenberg, P. S. Foster, M. J. Smyth, and C. R. Parish
Regulation of Carcinogenesis by IL-5 and CCL11: A Potential Role for Eosinophils in Tumor Immune Surveillance
J. Immunol.,
April 1, 2007;
178(7):
4222 - 4229.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Denburg and S. F. van Eeden
Bone marrow progenitors in inflammation and repair: new vistas in respiratory biology and pathophysiology.
Eur. Respir. J.,
March 1, 2006;
27(3):
441 - 445.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. Weller, S. J. Collington, J. K. Brown, H. R.P. Miller, A. Al-Kashi, P. Clark, P. J. Jose, A. Hartnell, and T. J. Williams
Leukotriene B4, an activation product of mast cells, is a chemoattractant for their progenitors
J. Exp. Med.,
June 20, 2005;
201(12):
1961 - 1971.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. C. E. Burdon, C. Martin, and S. M. Rankin
The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner
Blood,
March 15, 2005;
105(6):
2543 - 2548.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-Y. Eum, K. Maghni, B. Tolloczko, D. H. Eidelman, and J. G. Martin
IL-13 may mediate allergen-induced hyperresponsiveness independently of IL-5 or eotaxin by effects on airway smooth muscle
Am J Physiol Lung Cell Mol Physiol,
March 1, 2005;
288(3):
L576 - L584.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K.-I. Inoue, H. Takano, R. Yanagisawa, M. Sakurai, T. Ichinose, K. Sadakane, K. Hiyoshi, M. Sato, A. Shimada, M. Inoue, et al.
Role of Metallothionein in Antigen-Related Airway Inflammation
Experimental Biology and Medicine,
January 1, 2005;
230(1):
75 - 81.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Forssmann, I. Hartung, R. Balder, B. Fuchs, S. E. Escher, N. Spodsberg, Y. Dulkys, M. Walden, A. Heitland, A. Braun, et al.
n-Nonanoyl-CC Chemokine Ligand 14, a Potent CC Chemokine Ligand 14 Analogue That Prevents the Recruitment of Eosinophils in Allergic Airway Inflammation
J. Immunol.,
September 1, 2004;
173(5):
3456 - 3466.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. L. F. Sampaio, G. A. Rae, and M. d. G. M. O. Henriques
Effects of endothelin ETA receptor antagonism on granulocyte and lymphocyte accumulation in LPS-induced inflammation
J. Leukoc. Biol.,
July 1, 2004;
76(1):
210 - 216.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Parameswaran, R. Watson, G. M. Gauvreau, R. Sehmi, and P. M. O'Byrne
The Effect of Pranlukast on Allergen-induced Bone Marrow Eosinophilopoiesis in Subjects with Asthma
Am. J. Respir. Crit. Care Med.,
April 15, 2004;
169(8):
915 - 920.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Gregory, A. Kirchem, S. Phipps, P. Gevaert, C. Pridgeon, S. M. Rankin, and D. S. Robinson
Differential Regulation of Human Eosinophil IL-3, IL-5, and GM-CSF Receptor {alpha}-Chain Expression by Cytokines: IL-3, IL-5, and GM-CSF Down-Regulate IL-5 Receptor {alpha} Expression with Loss of IL-5 Responsiveness, but Up-Regulate IL-3 Receptor {alpha} Expression
J. Immunol.,
June 1, 2003;
170(11):
5359 - 5366.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Heinemann, R. Schuligoi, I. Sabroe, A. Hartnell, and B. A. Peskar
{Delta}12-Prostaglandin J2, a Plasma Metabolite of Prostaglandin D2, Causes Eosinophil Mobilization from the Bone Marrow and Primes Eosinophils for Chemotaxis
J. Immunol.,
May 1, 2003;
170(9):
4752 - 4758.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Sugimoto, M. Shichijo, T. Iino, Y. Manabe, A. Watanabe, M. Shimazaki, F. Gantner, and K. B. Bacon
An Orally Bioavailable Small Molecule Antagonist of CRTH2, Ramatroban (BAY u3405), Inhibits Prostaglandin D2-Induced Eosinophil Migration in Vitro
J. Pharmacol. Exp. Ther.,
April 1, 2003;
305(1):
347 - 352.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
B. Lamkhioued, S. G. Abdelilah, Q. Hamid, N. Mansour, G. Delespesse, and P. M. Renzi
The CCR3 Receptor Is Involved in Eosinophil Differentiation and Is Up-Regulated by Th2 Cytokines in CD34+ Progenitor Cells
J. Immunol.,
January 1, 2003;
170(1):
537 - 547.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Shen, P. M. O'Byrne, R. Ellis, J. Wattie, C. Tang, and M. D. Inman
The Effects of Intranasal Budesonide on Allergen-induced Production of Interleukin-5 and Eotaxin, Airways, Blood, and Bone Marrow Eosinophilia, and Eosinophil Progenitor Expansion in Sensitized Mice
Am. J. Respir. Crit. Care Med.,
July 15, 2002;
166(2):
146 - 153.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Mattes, M. Yang, S. Mahalingam, J. Kuehr, D. C. Webb, L. Simson, S. P. Hogan, A. Koskinen, A. N.J. McKenzie, L. A. Dent, et al.
Intrinsic Defect in T Cell Production of Interleukin (IL)-13 in the Absence of Both IL-5 and Eotaxin Precludes the Development of Eosinophilia and Airways Hyperreactivity in Experimental Asthma
J. Exp. Med.,
June 3, 2002;
195(11):
1433 - 1444.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Saito, K. Matsumoto, A. E. Denburg, L. Crawford, R. Ellis, M. D. Inman, R. Sehmi, K. Takatsu, K. I. Matthaei, and J. A. Denburg
Pathogenesis of Murine Experimental Allergic Rhinitis: A Study of Local and Systemic Consequences of IL-5 Deficiency
J. Immunol.,
March 15, 2002;
168(6):
3017 - 3023.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Mattes, M. Yang, A. Siqueira, K. Clark, J. MacKenzie, A. N. J. McKenzie, D. C. Webb, K. I. Matthaei, and P. S. Foster
IL-13 Induces Airways Hyperreactivity Independently of the IL-4R{alpha} Chain in the Allergic Lung
J. Immunol.,
August 1, 2001;
167(3):
1683 - 1692.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. J. Culley, A. Brown, D. M. Conroy, I. Sabroe, D. I. Pritchard, and T. J. Williams
Eotaxin Is Specifically Cleaved by Hookworm Metalloproteases Preventing Its Action In Vitro and In Vivo
J. Immunol.,
December 1, 2000;
165(11):
6447 - 6453.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Tomaki, L.-L. Zhao, J. Lundahl, M. Sjostrand, M. Jordana, A. Linden, P. O'Byrne, and J. Lotvall
Eosinophilopoiesis in A Murine Model of Allergic Airway Eosinophilia: Involvement of Bone Marrow IL-5 and IL-5 Receptor {alpha}
J. Immunol.,
October 1, 2000;
165(7):
4040 - 4050.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. P. Hogan, A. Mishra, E. B. Brandt, P. S. Foster, and M. E. Rothenberg
A critical role for eotaxin in experimental oral antigen-induced eosinophilic gastrointestinal allergy
PNAS,
June 6, 2000;
97(12):
6681 - 6686.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. Murphy, M. Baggiolini, I. F. Charo, C. A. Hebert, R. Horuk, K. Matsushima, L. H. Miller, J. J. Oppenheim, and C. A. Power
International Union of Pharmacology. XXII. Nomenclature for Chemokine Receptors
Pharmacol. Rev.,
March 1, 2000;
52(1):
145 - 176.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. W. Mould, A. J. Ramsay, K. I. Matthaei, I. G. Young, M. E. Rothenberg, and P. S. Foster
The Effect of IL-5 and Eotaxin Expression in the Lung on Eosinophil Trafficking and Degranulation and the Induction of Bronchial Hyperreactivity
J. Immunol.,
February 15, 2000;
164(4):
2142 - 2150.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. von Wasielewski, S. Seth, J. Franklin, R. Fischer, K. Hubner, M. L. Hansmann, V. Diehl, and A. Georgii
Tissue eosinophilia correlates strongly with poor prognosis in nodular sclerosing Hodgkin's disease, allowing for known prognostic factors
Blood,
February 15, 2000;
95(4):
1207 - 1213.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Cameron, P. Christodoulopoulos, F. Lavigne, Y. Nakamura, D. Eidelman, A. McEuen, A. Walls, J. Tavernier, E. Minshall, R. Moqbel, et al.
Evidence for Local Eosinophil Differentiation Within Allergic Nasal Mucosa: Inhibition with Soluble IL-5 Receptor
J. Immunol.,
February 1, 2000;
164(3):
1538 - 1545.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Zimmermann, B. L. Daugherty, J. M. Stark, and M. E. Rothenberg
Molecular Analysis of CCR-3 Events in Eosinophilic Cells
J. Immunol.,
January 15, 2000;
164(2):
1055 - 1064.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V Gouon-Evans, M. Rothenberg, and J. Pollard
Postnatal mammary gland development requires macrophages and eosinophils
Development,
January 6, 2000;
127(11):
2269 - 2282.
[Abstract]
[PDF]
|
|
|
|
|
|
|
R.-F. Guo, P. A. Ward, J. A. Jordan, M. Huber-Lang, R. L. Warner, and M. M. Shi
Eotaxin Expression in Sephadex-Induced Lung Injury in Rats
Am. J. Pathol.,
December 1, 1999;
155(6):
2001 - 2008.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. S. Foster
Allergic Networks Regulating Eosinophilia
Am. J. Respir. Cell Mol. Biol.,
October 1, 1999;
21(4):
451 - 454.
[Full Text]
|
|
|
|
|
|
|
M. E. Rothenberg
Eotaxin . An Essential Mediator of Eosinophil Trafficking into Mucosal Tissues
Am. J. Respir. Cell Mol. Biol.,
September 1, 1999;
21(3):
291 - 295.
[Full Text]
|
|
|
|
|
|
|
M. A. Giembycz and M. A. Lindsay
Pharmacology of the Eosinophil
Pharmacol. Rev.,
June 1, 1999;
51(2):
213 - 340.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Struyf, P. Proost, D. Schols, E. De Clercq, G. Opdenakker, J.-P. Lenaerts, M. Detheux, M. Parmentier, I. De Meester, S. Scharpe, et al.
CD26/Dipeptidyl-Peptidase IV Down-Regulates the Eosinophil Chemotactic Potency, But Not the Anti-HIV Activity of Human Eotaxin by Affecting Its Interaction with CC Chemokine Receptor 3
J. Immunol.,
April 15, 1999;
162(8):
4903 - 4909.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Teruya-Feldstein, E. S. Jaffe, P. R. Burd, D. W. Kingma, J. E. Setsuda, and G. Tosato
Differential Chemokine Expression in Tissues Involved by Hodgkin's Disease: Direct Correlation of Eotaxin Expression and Tissue Eosinophilia
Blood,
April 15, 1999;
93(8):
2463 - 2470.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Teran, M. Mochizuki, J. Bartels, E. L. Valencia, T. Nakajima, K. Hirai, and J.-M. Schröder
Th1- and Th2-Type Cytokines Regulate the Expression and Production of Eotaxin and RANTES by Human Lung Fibroblasts
Am. J. Respir. Cell Mol. Biol.,
April 1, 1999;
20(4):
777 - 786.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
L. Li, Y. Xia, A. Nguyen, Y. H. Lai, L. Feng, T. R. Mosmann, and D. Lo
Effects of Th2 Cytokines on Chemokine Expression in the Lung: IL-13 Potently Induces Eotaxin Expression by Airway Epithelial Cells
J. Immunol.,
March 1, 1999;
162(5):
2477 - 2487.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Sabroe, A. Hartnell, L. A. Jopling, S. Bel, P. D. Ponath, J. E. Pease, P. D. Collins, and T. J. Williams
Differential Regulation of Eosinophil Chemokine Signaling Via CCR3 and Non-CCR3 Pathways
J. Immunol.,
March 1, 1999;
162(5):
2946 - 2955.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Robinson, R. Damia, K. Zeibecoglou, S. Molet, J. North, T. Yamada, A. Barry Kay, and Q. Hamid
CD34+/Interleukin-5Ralpha Messenger RNA+ Cells in the Bronchial Mucosa in Asthma: Potential Airway Eosinophil Progenitors
Am. J. Respir. Cell Mol. Biol.,
January 1, 1999;
20(1):
9 - 13.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
I. Sabroe, D. M. Conroy, N. P. Gerard, Y. Li, P. D. Collins, T. W. Post, P. J. Jose, T. J. Williams, C. J. Gerard, and P. D. Ponath
Cloning and Characterization of the Guinea Pig Eosinophil Eotaxin Receptor, C-C Chemokine Receptor-3: Blockade Using a Monoclonal Antibody In Vivo
J. Immunol.,
December 1, 1998;
161(11):
6139 - 6147.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. T. Palframan, P. D. Collins, N. J. Severs, S. Rothery, T. J. Williams, and S. M. Rankin
Mechanisms of Acute Eosinophil Mobilization from the Bone Marrow Stimulated by Interleukin 5: The Role of Specific Adhesion Molecules and Phosphatidylinositol 3-Kinase
J. Exp. Med.,
November 2, 1998;
188(9):
1621 - 1632.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Sabroe, M. J. Peck, B. J. Van Keulen, A. Jorritsma, G. Simmons, P. R. Clapham, T. J. Williams, and J. E. Pease
A Small Molecule Antagonist of Chemokine Receptors CCR1 and CCR3. POTENT INHIBITION OF EOSINOPHIL FUNCTION AND CCR3-MEDIATED HIV-1 ENTRY
J. Biol. Chem.,
August 18, 2000;
275(34):
25985 - 25992.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract