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Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-stimulated HUVEC,
we found no selective accumulation of any particular leukocyte
subpopulations. In contrast, fewer leukocytes were recruited to
IL-4-stimulated HUVEC, but the recruitment was selective for
eosinophils. We examined the role of adhesion molecules in these
interactions and found that eosinophil recruitment was completely
blocked with an 4 integrin mAb at the shear rates
examined. A significant number of neutrophils were also recruited to
IL-4-stimulated HUVEC, and these interactions required P-selectin and
P-selectin glycoprotein ligand-1. Thus, whole blood perfusion over
cytokine-activated endothelium revealed that IL-4-stimulated HUVEC
support selective recruitment of eosinophils, whereas
TNF--stimulated HUVEC lack selectivity for any leukocyte
subclass. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, we used a technique recently described by Reinhardt and
Kubes (8) to examine leukocyte interactions with TNF-- or
IL-4-stimulated HUVEC. This technique does not rely on isolated
populations of leukocytes; instead, whole blood is perfused through the
flow chamber. After chasing the whole blood with buffer, interacting
leukocytes are examined and quantified using bright-field optics, and
the leukocytes recruited to the surface are identified by Wright-Giemsa
staining of the plate. This technique has the advantage of observing
interactions between leukocytes and endothelial cells in the context of
the whole blood. Additionally, this method allows for the immediate
identification of the leukocytes that have accumulated on a given
substrate (8), unlike current in vivo models.
We found that TNF--stimulated HUVEC recruited all classes of
leukocytes from whole blood; however, there was no selective
accumulation of any particular leukocyte subclass. In contrast,
IL-4-stimulated HUVEC recruited fewer leukocytes from the whole blood
than TNF--stimulated HUVEC; however, there was a 4-fold enrichment
in eosinophils. Surprisingly, IL-4-stimulated HUVEC also supported
significant accumulation of neutrophils. This manuscript details the
variable adhesion molecule combinations used by each leukocyte subclass
for optimal recruitment from whole blood.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-4 and TNF- were obtained from R & D Systems (Minneapolis,
MN). Anti-P-selectin mAbs G1 and S12 (9, 10), anti-E-selectin mAbs
ES1 (7), and anti-P-selectin glycoprotein ligand-1
(PSGL-1)3 mAbs PL1 and PL2 (11)
were all kindly provided by Dr. Rodger McEver (University of Oklahoma,
Oklahoma City, OK). Anti-VCAM-1 mAb 1.G11B1 and
anti-4 integrin mAb H2/1 were both purchased from
Serotec (Oxford, U.K.). Anti-CD16 mAb conjugated to paramagnetic beads
was purchased from Miltenyi (Auburn, CA).
Cell culture and isolation
HUVEC were isolated from individual umbilical cords and grown in Media 199 (M199) with 20% human serum as first passage cultures in 35-mm dishes (12). Neutrophils were isolated from normal human donors by dextran sedimentation, hypotonic lysis, and density centrifugation on lymphoprep 1077 (12). Eosinophils were isolated from granulocytes by negative selection with CD16 microbeads using magnetic cell separation (13).
Adhesion under flow conditions
HUVEC were treated with 20 ng/ml of IL-4 in M199 with 0.5%
human serum albumin (HSA) for 24 h or with 20 ng/ml TNF- in
M199/0.5% HSA for 6 h and then washed once with HBSS. Isolated
eosinophils or neutrophils (5 x 105/ml) in HBSS/0.5%
HSA were perfused through a parallel plate flow chamber at the desired
wall shear stresses, and leukocyte accumulation (rolling plus firmly
adherent) was determined as described (7, 11). Alternatively, freshly
drawn, heparinized whole blood was perfused through the flow chamber at
the specified shear rates for 4 min followed by perfusion of HBSS as
described (8). Shear rates were used for experiments with whole blood,
as determining the precise viscosity of blood to calculate wall shear
stress is problematic. The number of interacting leukocytes were
counted within 30 s of the HBSS perfusion using a 20x objective
and bright-field optics. All experiments were performed at 37°C. In
certain experiments, whole blood or HUVEC were preincubated for 10 min
with the specified mAb, and accumulation was assessed in the continued
presence of the mAb. mAbs were used at concentrations previously shown
to be optimal.
Analysis of accumulated leukocytes
Leukocytes accumulated on cytokine-stimulated HUVEC were characterized as described (8). Briefly, the inlet lines were removed from the flow chamber, allowing air to enter the chamber. This did not remove the interacting leukocytes, as we counted the number of leukocytes associated with the monolayer before and after the introduction of air into the system. The plates were removed from the chamber, allowed to air dry for 30 min, Wright-Giemsa stained, and then at least a 200-cell differential was performed in a blinded fashion. Using this technique, we were unable to differentiate monocytes from T cells due to leukocyte transmigration that led to distortion of the nucleus and cytoplasm, thus in all of the figures these cells are referred to as mononuclear cells (PBMCs).
Statistics
Statistical differences between experimental groups were evaluated using the two-tailed Mann-Whitney U test. Values of p < 0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- or IL-4-stimulated HUVEC
TNF-- and IL-4-stimulated HUVEC both express adhesion molecules
that support accumulation (rolling and adhesion) of isolated leukocyte
subpopulations under flow conditions. We and others have independently
examined the recruitment of neutrophils (14), eosinophils (15), T cells
(16), and monocytes (17) on TNF--stimulated HUVEC and found that all
of these cell types can adhere under flow conditions. In contrast,
IL-4-stimulated HUVEC support the interaction of isolated eosinophils
(18), T cells (19), and monocytes (6) but do not support neutrophil
adhesion (20) under flow conditions. Fig. 1
A compares neutrophil and
eosinophil accumulation on TNF-- or IL-4-stimulated HUVEC under flow
conditions. This data confirms previous observations, with eosinophils
accumulating on both of these surfaces, but neutrophils only
accumulating on TNF--stimulated HUVEC (Fig. 1A). Using
isolated eosinophils, we compared eosinophil accumulation on TNF--
and IL-4-stimulated HUVEC side by side. We found that isolated
eosinophils bind equally well to both TNF-- and IL-4-stimulated
HUVEC, with nearly identical shear dependence (Fig. 1B).
These data together show the potential interactions between leukocytes
and endothelial cells following cytokine stimulation. However, these
experiments do not address whether these interactions are favored in
the context of the whole blood.
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for
6 h or IL-4 for 24 h were placed in a parallel plate flow
chamber. Whole blood was perfused across these surfaces at the
specified shear rates and the number of accumulated leukocytes,
including both rolling and firmly adherent, was determined as described
in Materials and Methods. Leukocytes interacted with both
TNF-- and IL-4-stimulated HUVEC, but did not interact with control
HUVEC (Fig. 2). TNF--stimulated HUVEC
supported more leukocyte accumulation than IL-4-stimulated HUVEC at all
of the shear rates examined (Fig. 2 and data not shown). The increased
number of leukocytes recruited from whole blood as compared with
isolated leukocyte populations likely reflects the increased leukocyte
concentration in whole blood (4–10 x 106 cells/ml in
whole blood vs 0.5–1 x 106 cells/ml in isolated
leukocyte experiments) and/or the role of RBC in enhancing
leukocyte-endothelial cell interactions (21).
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-stimulated
HUVEC, but eosinophils are selectively recruited on IL-4-stimulated
HUVEC
We next examined the leukocyte subclasses recruited on
TNF--stimulated HUVEC and compared these numbers to the percentages
of each subclass normally found in the peripheral blood. This was done
to determine whether there was differential recruitment of particular
leukocyte subclasses. We found that neutrophils, PBMCs, and eosinophils
were all recruited to TNF--treated HUVEC (Fig. 3, A–F). The percentage of
each leukocyte subclass on TNF--stimulated HUVEC was virtually
identical to that found in the peripheral blood at all of the shear
rates examined. Therefore, dividing the percent of leukocytes
accumulated by the percent of leukocytes in the peripheral blood
generated a value close to 1.0 (Fig. 3, A, C, and
E). We refer to this value as the recruitment factor or
R-factor. This suggested that there was no selective recruitment of
leukocytes on TNF--stimulated HUVEC.
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).
The most striking observation was the 3- to 5-fold increase in
eosinophil recruitment during the 4 min of whole blood perfusion (Fig. 3, B, D, and F). The percentage of
eosinophils recruited remained constant at all of the shear rates
examined (Fig. 3, A, C, and E).
Isolated neutrophils did not interact with IL-4-stimulated HUVEC (Fig. 1A); however, neutrophils were efficiently recruited to
IL-4-stimulated HUVEC from whole blood in parallel experiments (Fig. 3). Unlike eosinophil accumulation, this recruitment was shear
dependent, as many neutrophils were recruited at lower shear rates and
few were recruited at higher shear rates. This decrease in percentage
translated to a decrease in the total number of neutrophils on the
surface. Based on the total cells recruited (Fig. 2), neutrophils
represented 186 cells/mm2 at 100 s-1 but only
represent 8 cell/mm2 at 400 s-1. Consistent
with this is the fact that IL-4-stimulated HUVEC preferentially
recruited neutrophils at a lower shear rate (R-factor > 1; Fig. 3B) but discriminated against neutrophils at higher shear
rates (R-factor < 1; Fig. 3F). Thus IL-4-stimulated
HUVEC support selective recruitment of eosinophils at all shear rates
but only support neutrophil recruitment at lower shear rates.
The role of adhesion molecules in leukocyte accumulation on
TNF-- or IL-4-stimulated HUVEC under flow conditions
TNF--stimulated HUVEC up-regulate VCAM-1, ICAM- 1, E-selectin
(reviewed in 1), and in some studies P-selectin (22), whereas
IL-4-stimulated HUVEC up-regulate VCAM-1 (23) and P-selectin (20). To
examine the role of these adhesion molecules in leukocyte recruitment
to either TNF-- or IL-4-stimulated HUVEC, we used a series of mAb to
inhibit leukocyte recruitment from whole blood. For these experiments,
we used an intermediate shear rate of 200 s-1. Fig. 4 shows that leukocyte recruitment on
TNF--stimulated HUVEC was dependent on both E-selectin and
VCAM-1/4 integrin interactions, and together these mAbs
almost completely blocked accumulation (Fig. 4A).
Anti-P-selectin and anti-PSGL-1 mAbs had no effect on recruitment
compared with their isotype-matched nonblocking control mAbs (data not
shown), suggesting that P-selectin does not participate in leukocyte
recruitment on this surface.
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4 integrins, or VCAM-1 and 4 integrins
together attenuated total leukocyte accumulation on IL-4-stimulated
HUVEC. Anti-P-selectin or PSGL-1 mAbs also decreased accumulation to
varying degrees, and an anti-P-selectin mAb together with an
anti-4 integrin mAb blocked almost all accumulation
(Fig. 4B). As expected, an anti-E-selectin mAb had no
effect on leukocyte accumulation on IL-4-stimulated HUVEC (data not
shown).
Effect of adhesion molecules on leukocyte recruitment profiles on
TNF-- or IL-4-stimulated HUVEC
We next determined the effect of adhesion molecule mAbs on the
recruitment of individual leukocyte classes from the whole blood. As in
Fig. 3, we performed between a 200- and 500-cell differential for each
experiment and determined the percentage of each leukocyte subclass on
the cytokine-treated HUVEC following mAb treatment. This data provided
two types of information. First, the effect of each mAb on the overall
recruitment of each leukocyte subclass could be determined. In
addition, this analysis allowed us to examine the effect of each mAb on
selective recruitment of particular leukocyte subpopulations.
We first examined leukocyte recruitment on TNF--stimulated HUVEC. We
found that an anti-E-selectin mAb decreased recruitment of all
leukocyte subclasses (Table I). However,
we found that an anti-E-selectin mAb did not effect the percentage of
each leukocyte subpopulation found on TNF--stimulated HUVEC (Table I). This suggests that E-selectin generally participates in the
recruitment of all leukocytes. In contrast an anti-VCAM-1 mAb
decreased recruitment of PBMCs both in total number and as a
percentage of the total leukocytes (Table I), but did not affect
neutrophil accumulation. So few eosinophils were recruited on
TNF--activated HUVEC that inhibition data was not statistically
significant.
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-treated HUVEC, we looked both at
the total numbers of leukocytes on this surface and at the percentage
each leukocyte subclass. VCAM-1 mAb decreased accumulation of all
leukocyte subclasses, including neutrophils (Fig. 5, A–C). Inhibition of total
neutrophils was unexpected; however, Reinhardt and Kubes have recently
shown that purified VCAM-1 can recruit neutrophils from whole blood
under flow conditions (8) and that all of this recruitment is inhibited
with an anti-4 integrin mAb. Our data are consistent
with this finding. An 4 integrin mAb alone or in
combination with an anti-VCAM-1 mAb also decreased the total
numbers of PBMC and neutrophils on IL-4-stimulated HUVEC, suggesting
that 4 integrin is interacting with VCAM-1 in this
system (Fig. 5, B and C).
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4 integrin mAb alone completely
inhibited eosinophil accumulation on IL-4-stimulated HUVEC (Fig. 5A). As, expected, the 4 integrin mAb in
combination with an anti-VCAM-1 mAb had the same effect on
eosinophil accumulation as the 4 integrin mAb alone
(Fig. 5A). The difference between a VCAM-1 mAb alone vs
4 integrin mAb alone may reflect a role for VCAM-1
domain 4 in eosinophil accumulation, as our VCAM-1 mAb only blocks
VCAM-1 domain 1 interactions (24, 25). Alternatively, another
4 integrin ligand may be expressed on this surface (26);
however, this ligand appears to be specific for eosinophils, as we did
not see this differential inhibition with PBMCs.
P-selectin and PSGL-1 mAbs almost completely blocked neutrophil
accumulation on IL-4-stimulated HUVEC (Fig. 5C). The ability
of neutrophils from whole blood to interact with P-selectin on
IL-4-stimulated HUVEC may reflect the role of RBC in enhancing
leukocyte-endothelial cell contacts, thus facilitating neutrophil
interactions with the low levels of P-selectin being expressed on these
HUVEC. Neither P-selectin nor PSGL-1 mAbs had any effect on PBMC
accumulation (Fig. 5B), consistent with data obtained from
whole blood rolling over P-selectin coated surfaces (8). Eosinophil
accumulation was attenuated with these mAbs, suggesting that P-selectin
and PSGL-1 play a partial role in eosinophil accumulation on
IL-4-stimulated HUVEC (Fig. 5A).
Fig. 6 compares the recruitment of each
leukocyte subclass on IL-4-stimulated HUVEC following mAb treatment. As
with Fig. 3, the data are presented both as the percent of each
leukocyte subclass present on IL-4-stimulated HUVEC and as the R-factor
based on the percent of each leukocyte in the peripheral blood. These
data reflect the role specific adhesion molecules play in selective
recruitment of particular leukocyte subclasses. VCAM-1 in combination
with an anti-4 integrin mAb dramatically decreased
PBMC recruitment (Fig. 6, B and E). In contrast,
neither VCAM-1 nor 4 integrins had any effect on
neutrophil recruitment; instead, P-selectin and PSGL-1 were responsible
for selective neutrophil recruitment (Fig. 6, C and
F). Eosinophils were unique in that 4
integrins alone were responsible for selective recruitment (Fig. 6, A and D). As with accumulation, this may reflect
differential utilization of VCAM-1 domain 4 by 4
integrins on eosinophils or may suggest that there is an
4 integrin ligand other than VCAM-1 on IL-4-stimulated
HUVEC responsible for selective eosinophil recruitment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In vivo models of airway hyperresponsiveness have demonstrated a role
for Th2 cytokines in the development of eosinophilia and airway
hyperresponsiveness (30, 31). In particular, IL-4 (32), IL-13 (33, 34),
and IL-5 (35) have all been shown to participate in the recruitment of
eosinophils. Furthermore, roles for adhesion molecules such as VCAM-1,
4 integrins (36) and the endothelial selectins (37, 38)
have been suggested in mediating the initial attachment of leukocytes
in these and other models of allergic inflammation. These adhesion
molecules have been suggested to play either a direct role in
eosinophil infiltration or an indirect role by blocking the recruitment
of Th2 cells and, by extension, the infiltration of eosinophils.
The molecular mechanisms that govern the selective recruitment of
eosinophils have also been examined using in vitro models of
inflammation. In these studies, isolated eosinophils have been perfused
over endothelial cells stimulated with cytokines under flow conditions
(15, 18, 39, 40). Using this model, two cytokines have come to the
forefront for their ability to up-regulate VCAM-1 and bind eosinophils:
TNF- and IL-4.
TNF- is a multifunctional cytokine that plays a key role in the
pathogenesis of both acute and chronic diseases including septic shock,
adult respiratory distress syndrome, rheumatoid arthritis, and asthma
(reviewed in 41). TNF- can be generated by a multitude of cells
and exerts its effects by interacting with at least two classes of
receptors present on many cells, including endothelial cells (42).
TNF--stimulation of HUVEC results in increased expression of several
adhesion molecules including E-selectin, VCAM-1, ICAM-1, and P-selectin
(reviewed in 1). IL-4 is a cytokine frequently associated with the
development of atopy and allergic inflammation (43). IL-4 is produced
primarily by Th2 cells, but is also synthesized and released by mast
cells and eosinophils (43). IL-4 maintains the Th2 phenotype of
CD4+ T cells, leads to class switching in B cells, and
stimulates HUVEC (44, 45, 46, 47). IL-4-stimulated HUVEC up-regulate adhesion
molecules such as VCAM-1 (23) and P-selectin (20). TNF- and IL-4 are
both commonly used in vitro to examine leukocyte-endothelial cell
adhesion and activation, and HUVEC treated with either of these
cytokines have been shown to effectively recruit isolated eosinophils
under flow conditions (15, 18). However, these experiments have not
examined the ability of these cytokines to mediate the selective
accumulation of eosinophils.
In this study, we found that TNF--stimulated HUVEC accumulated a
tremendous number of leukocytes from whole blood. This recruitment used
both E-selectin and VCAM-1, but not P-selectin. Despite the numbers of
leukocytes recruited to TNF--stimulated HUVEC, there was no
selective increase in any one leukocyte subclass. This suggests that
TNF- alone may act in a general way to recruit leukocytes to the
vessel wall. Once leukocytes are rolling along the endothelium, other
factors such as chemokines or additional cytokines may modulate
subsequent firm adhesion and transmigration of specific leukocyte
subpopulations into sites of inflammation.
In this study, we also examined whole blood interactions with IL-4-stimulated HUVEC and found that IL-4-stimulated HUVEC supported selective accumulation of eosinophils from the peripheral blood. A 4.5-fold increase in eosinophil accumulation occurred in the few minutes that whole blood was perfused over this surface. One can envision that over a 24-h period this would lead to a profound increase in eosinophil recruitment. At higher shear stresses, there was also a selective increase in PBMC recruitment. These data are consistent with IL-4 playing a role in selective recruitment of these cells in vivo. At the same time, it is striking that this level of selectivity was seen in a model system in which only the endothelial cells were present. In the context of the whole animal, for example during hypersensitivity, other cell types such as mast cells and resident T cells may further amplify this response by the synthesis of chemokines and other chemoattractants.
The 4 integrins alone were responsible for the selective
recruitment of eosinophils (Fig. 6). This is in contrast to PBMCs,
where both VCAM-1 and 4 integrins affected selective
PBMC recruitment (Fig. 6). The 4 integrins can bind to
two domains on VCAM-1, domains 1 and 4 (24, 25), but our VCAM-1 mAb
only binds to domain 1. Abe et al. recently demonstrated that T cells
use domain 1 for attachment under flow conditions and then use domain 4
to stabilize these interactions (48). Eosinophil utilization of domains
1 and 4 under flow conditions has not been examined, and it may be that
eosinophils are interacting with domain 4 on VCAM-1 in these
experiments. Alternatively, IL-4-stimulated HUVEC may express another
ligand for eosinophil 4 integrins as has been suggested
by Vonderheide et al. (26). Thus, these data show that P-selectin can
mediate the attachment of eosinophils under flow conditions in the
context of whole blood, but it is the engagement of the
4 integrins that dictates the selective accumulation of
eosinophils in this system.
Unlike isolated neutrophils, neutrophils from whole blood were also recruited on IL-4-stimulated HUVEC at lower shear rates, and these interactions required P-selectin and PSGL-1. Several factors may play a role in these interactions. First, increased encounters between neutrophils and the vessel wall due to the presence of RBC (21) may facilitate interactions between neutrophils and the low levels of P-selectin present on the surface of IL-4-stimulated HUVEC. Interestingly, visual observation of these plates after staining suggests that PBMCs and eosinophils were actively spreading and transmigrating on IL-4-stimulated HUVEC; whereas, neutrophils remained rounded on the surface (data not shown). Because P-selectin mediates only rolling, it is tempting to conclude that neutrophils were only participating in rolling interactions with IL-4-stimulated HUVEC. Indeed, Warnock et al. demonstrated that neutrophils roll in lymph nodes but unlike lymphocytes do not become firmly adherent (49). Additionally, P-selectin expressed on platelets in suspension or platelets accumulated on the plate may act to recruit neutrophils. Recently, Diacovo et al. have demonstrated that P-selectin expressed on platelets can facilitate leukocyte interactions with the vessel wall in vivo (50). Although we did see a few platelets binding to the plate in areas of endothelial cell retraction, we never observed leukocytes interacting with these platelets. Furthermore, blood was maintained in heparin to prevent platelet activation; thus, it is unlikely that activated platelets were responsible for neutrophil accumulation.
Surprisingly, VCAM-1 and 4 integrins also decreased the
total accumulation of neutrophils in this system (Fig. 5). These
interactions were not observed using isolated populations of
neutrophils (Fig. 1A) in side-by-side experiments. However,
unactivated neutrophils have been shown to interact with purified
VCAM-1 using whole blood perfusion (8). This may reflect a small
subpopulation of immature neutrophils that still express
4 integrins. Consistent with this, we frequently find
1–2% of neutrophils expressing 4 integrins using flow
cytometry (data not shown).
These data show that IL-4-stimulated HUVEC support the selective
accumulation of eosinophils from whole blood in the absence of signals
from other cell types such as mast cells, resident Th2 cells, or
macrophages. In contrast, TNF- stimulated HUVEC generally recruit
all types of leukocytes from the whole blood and may rely on signals
from the tissue to result in selective accumulation of any particular
class of leukocytes.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kamala D. Patel, Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. E-mail address:
3 Abbreviations used in this paper: PSGL-1, P-selectin glycoprotein ligand-1; M199, media 199; HSA, human serum albumin; R-factor, recruitment factor.
Received for publication November 5, 1998. Accepted for publication March 2, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4 integrin have distinct roles in eosinophil tethering and arrest on vascular endothelial cells under physiological flow conditions. J. Immunol. 159:3929.[Abstract]
-activated vascular endothelium under flow in vitro. J. Immunol. 157:326.[Abstract]
-activated endothelium: augmentation by erythrocyte. Biophys. J. 69:2131.[Medline]
-activated vascular endothelium under flow. J. Exp. Med. 181:1179.4ß1). J. Cell Biol. 124:601.4 integrin counter-receptor on stimulated endothelium. J. Exp. Med. 175:1433.4 integrins in the lung. Ann. NY Acad. Sci. 796:113.[Medline]
4 integrins to eosinophil trafficking in allergic and nonallergic inflammatory reactions in skin. J. Immunol. 161:2516. (TNF-)-induced cell adhesion to human endothelial cells is under dominant control of one TNF receptor type, TNF-R55. J. Exp. Med. 177:1277.4 integrin-dependent adhesion under static and flow conditions are differentially regulated. J. Immunol. 157:5061.[Abstract]
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, Not significant as compared with VCAM-1 or
