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Departments of
*
Otolaryngology and
Immunology and Parasitology, Yokohama City University School of Medicine, Yokohama, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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4 integrin on monocytes.
However, the mean channel fluorescence value for binding Cy2-conjugated
soluble VCAM-1 to P-selectin-bound monocytes was slightly more than
that for binding Cy2-conjugated soluble VCAM-1 to untreated monocytes.
Under flow conditions, the number of P-selectin-bound monocytes bound
to VCAM-1 was much higher than that of untreated monocytes bound to
VCAM-1. These bindings were abolished by pretreatment of untreated
monocytes and P-selectin-bound monocytes with anti-VCAM-1 mAb or
anti-4 integrin mAb. Furthermore, P-selectin binding
to monocytes increased shear resistance and thus increased the adhesive
strength of monocytes to VCAM-1. These findings indicate that
P-selectin binding to monocytes enhances the adhesive interaction of
monocytes with VCAM-1. It is suggested that P-selectin glycoprotein
ligand-1/P-selectin interaction and 4 integrin/VCAM-1
interaction can act sequentially in the adhesion cascade that regulates
monocyte trafficking to inflammatory and atherosclerotic
lesion. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B that is required for the production of
monocyte chemotactic protein-1 and TNF- (2, 4). In addition, VCAM-1,
a member of the Ig superfamily expressed on the surface of activated
endothelial cells, plays an important role in T cell rolling and arrest
(6). Luscinskas et al. (7) found that P-selectin could mediate primary
tether and rolling of CD4+ T cells to
TNF--stimulated endothelial cells and that VCAM-1 is involved in the
subsequent arrest. Monocyte adhesion to vascular endothelium and migration to vascular endothelial lining play important roles in chronic inflammation, immune reaction, and atherosclerosis. In vitro studies have examined monocyte interactions with cytokine-activated endothelium (8, 9). Monocyte adhesion to cytokine-activated HUVEC involved sequential and overlapping adhesion pathway, including the selectins (L-selectin, and P-selectin), VCAM-1, VLA-4, ß2 integrin, ICAM-1, and platelet endothelial adhesion molecule-1. However, E-selectin was not involved in these systems. In vivo studies indicated that monocyte migration to inflamed skin (10) or joints in arthritic rats (11) was inhibited by P-selectin mAb, but not by E-selectin mAb. Furthermore, the accumulation of monocytes in arterial intima, which is thought to be one of the characteristic features of early atherosclerotic lesions, consists of multiple molecular mechanisms involving chemoattractants and adhesion molecules (12, 13, 14, 15, 16, 17, 18, 19, 20, 21). The expression of P-selectin, E-selectin, VCAM-1, and ICAM-1 was up-regulated in established lesions of atherosclerosis (14, 15, 16, 17, 18, 19, 20).
To better understand the sequential monocyte adhesive interactions with
endothelium at inflammatory and atherosclerotic lesions, we focused on
PSGL-1/P-selectin interaction and 4
integrin/VCAM-1 interaction. PSGL-1/P-selectin interaction plays an
important role in rolling of leukocytes, and 4
integrin/VCAM-1 interaction plays an important role in tethering,
rolling, and arrest of leukocytes (6, 7, 9, 22, 23). However, it is not
clear whether these two interactions can act sequentially in an
adhesion cascade of monocytes. The effect of P-selectin binding on the
adhesive interaction with VCAM-1 through 4
integrin in monocyte adhesion to endothelium has not been reported. In
this study we examined the tethering and rolling of monocytes on VCAM-1
molecules and analyzed the effect of P-selectin binding to monocytes on
the adhesive interaction with VCAM-1 under flow conditions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Purified platelet P-selectin, inhibitory anti-P-selectin mAb
(G1, mouse IgG1), noninhibitory anti-P-selectin mAb (S12, mouse
IgG1), inhibitory anti-P-selectin
glycoprotein ligand-1 (anti-PSG1-1)3 mAb (PL-1, mouse IgG1
), and noninhibitory anti-PSGL-1 mAb (PL-2, mouse IgG1 ) were
gifts from Drs. K. L. Moor and R. P. McEver (University of
Oklahoma Health Sciences Center, Oklahoma City, OK). UCHT-1
(anti-CD3, IgG1 ), M5E2 (anti-CD14, IgG2a ), 3G8
(anti-CD16, IgG1) were obtained from PharMingen (San Diego, CA).
HP2/1 (inhibitory anti-4 integrin, IgG1)
was purchased from Immunotech (Westbrook, ME). FITC-labeled rabbit
anti-mouse Ig was purchased from Dako (Glostrup, Denmark). Goat
anti-mouse IgG MACS beads were purchased from Miltenyi Biotec
(Auburn, CA). Soluble VCAM-1 was provided by Dr. R. Lobb (Biogen,
Cambridge, MA).
Fractionation of cells
Mononuclear cells were isolated from heparinized peripheral blood collected by venipuncture from healthy donors. The blood was diluted with an equal volume of 0.9% NaCl and layered over Ficoll/Hypaque-Lymphoprep (Nycomed, Oslo, Norway). The mononuclear cells were harvested. For purification of monocytes, the mononuclear cells were incubated with anti-human CD3, CD16, and CD19 mAbs for 30 min at 4°C. The cells were washed twice in PBS with 1% BSA and further incubated with goat anti-mouse IgG-conjugated magnetic beads for 30 min at 4°C. The cells were then washed twice and applied to a magnetic cell separator column to deplete T cell, B cells, and NK cells. The negative fraction was harvested. Flow cytometric analysis revealed that the resulting monocyte population contained >93% CD14+, <3% CD3+, <2% CD16+, and <2% CD19+. Neutrophils were isolated from heparinized blood using Monopoly resolving medium (Dainippon Pharmaceutical, Osaka, Japan). Neutrophils were 90% pure as assessed by Wright-Giemsa staining.
FACS analysis of monocytes
For direct immunofluorescence, monocytes were incubated with
PE-conjugated anti-4 integrin mAb for 30
min at room temperature. Furthermore, to analyze soluble VCAM-1 binding
to monocytes, recombinant soluble VCAM-1 was labeled using the
FluoroLink-Ab Cy2 labeling kit (Amersham, Arlington Heights, IL).
Monocytes (106 cells) were incubated with
Cy2-conjugated soluble VCAM-1 (50 µl, 10 µg/ml) for 30 min at room
temperature. For indirect immunofluorescence, monocytes
(106 cells) were incubated with anti-PSGL-1
mAb (PL-1). Bound Ab was detected with FITC-conjugated anti-mouse
Ig. Furthermore, monocytes (106 cells) were
incubated with purified P-selectin (50 µl, 10 µg/ml) for 30 min at
4°C in HBSS/1% FCS/0.1% NaN3, and washed
twice with HBSS/1% FCS/0.1% NaN3. Subsequently,
the cells were incubated with anti-P-selectin mAb (S12), washed
twice with HBSS/1% FCS/0.1% NaN3, and stained
with FITC conjugated anti-mouse Ig. Expression was analyzed on a
Becton Dickinson FACScan with CellQuest analysis software (Becton
Dickinson, Mountain View, CA).
Attachment of monocyte to VCAM-1 under flow conditions
The model of flow conditions was described previously (24, 25). Briefly, a tube was attached to the end of a glass capillary tube, and the tube was connected to a syringe pump (TERUMO, Tokyo, Japan) fitted with a 50-ml syringe to establish laminar flow. The wall shear stress was calculated by Poiseuille’s law of Newtonian fluids, with viscosity of 0.01 (at room temperature). The wall shear stress in dynes per square centimeter = [(mean flow velocity x 8)/tube diameter)] x viscosity. The tube was mounted on an Olympus (Tokyo, Japan) inverted microscope. Interaction of monocyte with VCAM-1 was observed and videotaped for 3 min. Soluble VCAM-1 was diluted with 50 mM Tris-HCl (pH 8.0) to a final concentration of 10 µg/ml and coated in capillary tubes overnight at 4°C. These capillary tubes were washed three times with PBS. Thereafter, 50 µl of PBS with 5% human serum albumin was added to each capillary tube to block nonspecific binding sites, and the capillaries were incubated for 1 h at room temperature.
In the flow system, 1 x 106 monocytes/ml of binding medium with 2 mM Ca2+ and 1 mM Mg2+ were flowed across in the capillary tube using a syringe pump at room temperature. In some cases monocytes were preincubated with purified P-selectin (10 µg/ml). Untreated monocytes and P-selectin bound monocytes were flowed across in the VCAM-1-coated capillary tubes, and the adhesion of monocytes to VCAM-1 was determined at variable rates of shear stress. The number of adherent cells was examined by counting four to six fields (x200) under an inverted microscope during the entire 3-mim experiment.
Evaluation of total adherent cells and rolling or arrested cells, and primary tethering or secondary tethering
The number of total adherent cells was defined as the number of cells that arrested and remained rolling at the end of the 3-min observation period. For the analysis of tethered cell behavior, the movement of each tethered cell was noted for the first 30 s of the observation after it first tethered. During this period, the majority of tethered cells were primary. Among the cells that remained adherent, cells that were displaced less than or more than one cell diameter for 30 s were defined as arrested or rolling cells, respectively.
Quantification of primary and secondary tethered cells was determined as described previously (26, 27). Tethering events were observed using frame-by-frame analysis of the 3 min perfusion. All tethers that formed during this interval were counted. Cells that tethered directly to the bottom of the VCAM-1-coated tubes were quantitated as primary tether accumulation, and cells that tethered to the bottom of the VCAM-1-coated tubes after first interacting with adherent cell through an interleukocyte tether were quantitated as secondary tether accumulation.
Detachment assay (measurement of adhesion strength)
Detachment assays were performed on cells after they had tethered at 0.3 dyn/cm2 to allow accumulation of tethered cells for 2 min. The shear flow was increased every 10 s to a maximum of 20 dyn/cm2. The number of cells that remained bound at the end of each 10-s interval was determined.
For Ab inhibition assays, the VCAM-1-coated capillary tube was first
treated with anti-VCAM-1 mAb (20 µg/ml for 30 min) or
isotype-matched control Ab. Furthermore, monocytes were treated with
anti-4 integrin mAb (20 µg/ml for 30
min) or isotype-matched control Ab in some experiments.
The data shown in this study are the results of representative experiments among more than three independent experiments. The error bar represents the SD. The results are expressed as the mean ± SD per field.
Statistical analysis
Data were compared through ANOVA using the unpaired Student’s t test, and p < 0.05 was considered to represent a significant difference between group means.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We analyzed the expression of PSGL-1 on monocytes and the binding
of platelet-derived P-selectin to monocytes. Most monocytes expressed
PSGL-1 recognized by PL-1 mAb (Fig. 1
A). Further, we analyzed
P-selectin binding to monocytes for detection of the functional form of
PSGL-1. We observed that most monocytes bound P-selectin (Fig. 1B). P-selectin binding to monocytes were abolished by
anti-P-selectin mAb G1 (20 µg/ml) or anti-PSGL-1 mAb (PL-1;
20 µg/ml; Fig. 1, B and C), but not by
anti-P-selectin mAb S12 (data not shown) or anti-PSGL-1 mAb
(PL-2; Fig. 1C).
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We analyzed the expression of 4 integrin
on monocytes and determined whether P-selectin binding enhanced the
amount of 4 integrin expressed on monocytes.
In some experiments monocytes were incubated with P-selectin (10
µg/ml). Untreated monocytes and P-selectin-bound monocytes were
stained with PE-conjugated anti-4 integrin
mAb. Most untreated monocytes and most P-selectin-bound monocytes
expressed 4 integrin. The mean channel
fluorescence value for 4 integrin on
P-selectin-bound monocytes was similar to that on untreated monocytes.
Thus, P-selectin binding did not alter the expression of
4 integrin on monocytes (Fig. 2, A and B).
Further, we analyzed soluble VCAM-1 binding to untreated monocytes and
P-selectin-bound monocytes to detect expression of
4 integrin that could bind VCAM-1. Soluble
VCAM-1 was conjugated with Cy2 as described in Materials and
Methods. Most untreated monocytes and most P-selectin-bound
monocytes bound VCAM-1 (Fig. 2C). The mean channel
fluorescence value for binding VCAM-1 on untreated monocytes was
88 ± 10.8 (Fig. 2C, line a). On the other hand, mean
fluorescence value for binding VCAM-1 on P-selectin-bound monocytes was
138 ± 28.6 (Fig. 2C, line b). The difference between
these two groups was statistically significant. Thus, these data
suggested that P-selectin binding to monocytes increased the amount of
4 integrin that could bind VCAM-1. Neutrophils
that cannot bind VCAM-1 were used as a negative control for
Cy2-conjugated soluble VCAM-1 (Fig. 2D). Binding of soluble
VCAM-1 to untreated monocytes and P-selectin-bound monocytes was
inhibited by the presence of anti-VCAM-1 mAb (Fig. 2C,
lines c and d).
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We examined the monocyte adhesive activity to VCAM-1 under flow
conditions and analyzed the effect of P-selectin binding on the
adhesive activity of monocytes to VCAM-1. After 3 min of perfusion, the
total adherent monocytes were counted. Untreated monocytes adhered to
VCAM-1-coated tubes under shear stress between 0.5–1.5
dyn/cm2, and P-selectin-bound monocytes adhered
to VCAM-1-coated tubes under shear stress between 0.5–2.0
dyn/cm2 (Fig. 3).
Above 2.5 dyn/cm2, the binding of untreated
monocytes and that of P-selectin-bound monocytes to VCAM-1 were not
significant. The number of P-selectin-bound monocytes bound to VCAM-1
was higher than that of untreated monocytes under shear stress <2.0
dyn/cm2. The interactions of untreated monocytes
and P-selectin-bound monocytes with VCAM-1 were completely abolished by
pretreatment of the VCAM-1-coated tubes with anti-VCAM-1 mAb.
Treatment with isotype-matched mAb had no inhibitory effect (data not
shown). These data suggested that P-selectin binding to monocytes
enhanced the adhesion of the monocytes to VCAM-1 under shear
stress.
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4
integrin mAb on the binding of untreated monocytes and P-selectin-bound
monocytes to VCAM-1. The interactions of untreated monocytes and
P-selectin-bound monocytes with VCAM-1 were abolished by pretreatment
with anti-4 integrin mAb (data not
shown). The behavior of tethers of untreated monocytes and of tethers of P-selectin-bound monocytes to VCAM-1
We analyzed the behavior of tethered untreated monocytes and
tethered P-selectin-bound monocytes after the initial tether under
shear stress at 0.5 and 1.0 dyn/cm2. About 85%
of tethered untreated monocytes arrested and about 15% of tethered
untreated monocytes rolled under shear stress at 0.5
dyn/cm2, and about 80% of tethered untreated
monocytes arrested and about 20% of tethered untreated monocytes
rolled under shear stress at 1.0 dyn/cm2 (Fig. 4A). In contrast, almost all
tethered P-selectin-bound monocytes arrested under shear stress at 0.5
and 1.0 dyn/cm2 (Fig. 4B), implying
activation of 4 integrin by preincubation with
P-selectin.
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We analyzed primary and secondary tethers of untreated and
P-selectin-bound monocytes to VCAM-1. Monocytes (1 x
106/ml) were flowed across in the VCAM-1-coated
capillary tube using a syringe pump for 3 min under shear stress at 1.0
dyn/cm2. Adherent monocytes were defined as the
total accumulation of primary or secondary tethered cells during 3-min
perfusion. The number of primary tethered P-selectin-bound monocytes to
VCAM-1 was much higher than that of primary tethered untreated
monocytes (Fig. 5). On the other hand,
the difference between the number of secondary tethered
P-selectin-bound monocytes to VCAM-1 and that of secondary tethered
untreated monocytes was not significant. Furthermore, P-selectin
binding to monocytes reduced the secondary capture (monocyte-monocyte
adhesion). The majority of monocyte-monocyte collision was elastic
(data not shown). These data indicated that P-selectin binding to
monocytes increased the number of primary tethers of monocytes.
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We analyzed the adhesive strength of monocytes to
VCAM-1 and the effect of P-selectin binding on the adhesive strength of
monocytes to VCAM-1. Cells were allowed to tether to VCAM-1 under shear
stress at 0.3 dyn/cm2 for 2 min, and then shear
was initiated and increased. The number of cells that remained bound
was determined at each shear stress. The percentage of the remaining
P-selectin-bound monocytes was much higher than that of untreated
monocytes under shear stress above 4.0 dyn/cm2
(Fig. 6). These data suggested that
P-selectin binding to monocytes increased shear resistance and thus
increased the adhesive strength of monocytes to VCAM-1.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4 integrin
expressed on leukocytes can support tethering and rolling.
Lymphoma-derived and leukemia-derived cell lines, human T cells, and
4 integrin-transfected cells tethered in shear
flow and then rolled, arrested through binding of
4 integrin to VCAM-1 on the wall of a flow
chamber (6, 22, 23). Jones et al. (6) reported that <10% of
interacting T cells rolled on VCAM-1-transfected L cells, and majority
of T cells arrested immediately on VCAM-1 transfectant under shear
stress at 2.0 dyn/cm2. Alon et al. (23) reported
that several different patterns of T cell behavior were seen in the
interaction of T cells with immobilized VCAM-1 under flow conditions
after tethering. Some of the T cells rolled on VCAM-1, others arrested
after rolling, and others arrested immediately. The majority of K562
cells transfected with 4 integrin rolled on
VCAM-1 (23). More than 95% of tethered eosinophils arrested
immediately after tethering to VCAM-1 (28). In our data, most monocytes
expressed 4 integrin. Monocytes tethered to
VCAM-1 under flow conditions (Fig. 3
). Alon et al. (26) reported that
monocytes could tether to VCAM-1 through 4
integrin. This monocyte accumulation on VCAM-1 consisted of a large
number of secondary tethers and a small number of primary tethers. Most
of the tethered monocytes arrested on VCAM-1, although a few monocytes
rolled (Fig. 4). The reason for these differences in tethered cell
behavior may be attributed to functional differences between
4 integrins on T cells and K562 cells
transfected with 4 integrin and those on
eosinophils and monocytes. Furthermore, it was reported that VCAM-1 expressed on AdRSVrVCAM-1 transduced HUVECs supported not only monocyte rolling and arrest, but also firm adhesion and transmigration under shear stress (29). Thus, it is suggested that VCAM-1 molecules expressed on endothelium play an important role in monocyte migration into target sites.
PSGL-1 is the major leukocyte ligand for P-selectin. PSGL-1 is
expressed on hemopoietic cells (30). Most lymphocytes expressed PSGL-1,
but about 15% of lymphocytes expressed the form that could bind
P-selectin (data not shown). On the other hand, most monocytes bound
P-selectin (Fig. 1B). These data indicated that most
monocytes expressed the high affinity form of PSGL-1 for P-selectin.
Cooper et al. (2) reported that purified platelet-derived P-selectin
binding stimulated phagocytosis of human neutrophils and influenced
ß2 integrin function. Furthermore, Hidari et
al. (31) reported that ligation of PSGL-1 expressed on neutrophils
using anti-PSGL-1 mAb increased tyrosine phosphorylation of
proteins. On the other hand, Elasted et al. (3) reported that monocytes
tethering by P-selectin regulated platelet-activating factor synthesis
and phagocytosis, but platelet-derived P-selectin binding to monocytes
did not alter platelet-activating factor synthesis induced by calcium
ionophore. Furthermore, incubation of neutrophils with soluble
P-selectin or on immobilized P-selectin has been reported to inhibit
the responses of neutrophils, including superoxide generation and
adhesiveness mediated by CD11/CD18 integrins (32, 33, 34). Chen et al. (35)
reported that Mn2+ and PMA stimulation enhanced
the ability of VLA-4 on Jurkat cells and increased the resistance to
detachment from VCAM-1 by shear flow. Forty percent of wild-type Jurkat
cells arrested immediately, and 25% of tethered wild-type cells
arrested spontaneously within 10 s following tethering on VCAM-1.
On the other hand, energy-deleted Jurkat cells continued to roll
on VCAM-1 (35). We found that platelet-derived P-selectin binding
increased the number of adherent monocytes on immobilized VCAM-1 under
flow conditions and clearly increased the adhesive strength of
monocytes to VCAM-1 (Figs. 2, 3, and 6). Almost all P-selectin-bound
monocytes arrested under shear stress. Our data indicated that
P-selectin binding enhanced 4 integrin
function on monocytes. The 4 integrin on
resting monocytes did not appear to be fully activated.
Platelet-derived P-selectin used in our study is of the oligomeric form
(36). These data suggested that oligomeric binding of P-selectin to
monocytes or ligation of PSGL-1 through P-selectin enhanced and
activated the function of 4 integrin.
P-selectin binding to monocytes increased the number of primary
tethers. On the other hand, the difference between the number of
secondary tethers of P-selectin-bound monocytes and that of untreated
monocytes was not significant (Fig. 5). L-selectin/PSGL-1 interaction
plays an important role in neutrophil/neutrophil and monocyte/monocyte
interactions and secondary tethers of these cells (26, 37, 38).
Anti-PSGL-1 mAb (KPL-1) blocked monocyte rolling and transient
attachment on adherent monocytes (38). We found that P-selectin binding
to monocytes through PSGL-1 did not alter the number of secondary
tethers of monocytes. These data suggest that P-selectin binding
activated ligands for L-selectin other than PSGL-1.
Monocyte adhesion to vascular endothelium and migration to vascular
endothelial lining play important roles in chronic inflammation, immune
reaction, and atherosclerosis. P-selectin is expressed on activated
platelets or activated endothelium at sites of inflammation or tissue
injury. In vivo studies indicated that monocyte migration to skin
inflammation or joints in arthritic rats were dependent on P-selectin
(10, 11). Furthermore, P-selectin is expressed on atherosclerotic
endothelial cells (14, 16). VCAM-1 is expressed on cytokine-activated
endothelium and is expressed on atherosclerotic endothelium (14, 15, 17). P-selectin/PSGL-1 interaction plays an important role in initial
step rolling of T cells and neutrophils (7, 39).
4 integrin/VCAM-1 interaction plays an
important role in leukocyte tethering, rolling, and subsequent
arrest (6, 7, 9, 22, 23). In addition, VCAM-1 expressed on
unactivated endothelium supports monocyte firm adhesion and
transmigration (29).
We demonstrated that P-selectin binding to monocytes enhanced the
adhesion of monocytes to VCAM-1 under flow conditions. Our findings
indicate that primary tethering of monocytes to P-selectin can
influence the subsequent adhesion of 4
integrin/VCAM-1 interaction, and can regulate monocyte migration into
sites of inflammation, tissue injury, or atherosclerosis.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Tadayuki Yago, Department of Otolaryngology, Yokohama City University, School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama, 236, Japan.
3 Abbreviations used in this paper: PSGL-1, P-selectin glycoprotein ligand-1; VLA-4, very late Ag-4.
Received for publication January 11, 1999. Accepted for publication April 14, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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secretion. J. Clin. Invest. 95:2297.
mß2) on human neutrophils. J. Exp. Med. 173:1493.-activated vascular endothelium under flow. J. Exp. Med. 181:1179.-activated vascular endothelium under flow in vitro. J. Immunol. 156:326.
4 integrin-dependent adhesion under static and flow conditions are differentially regulated. J. Immunol. 157:5061.[Abstract]
4 integrin have distinct roles in eosinophil tethering and arrest on vascular endothelial cells under physiological flow conditions. J. Immunol. 159:3929.[Abstract]
-activated endothelium under flow in vitro. J. Immunol. 161:2501.This article has been cited by other articles:
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