Departments of 1 Genomics and Pathobiology and 2 Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019
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ABSTRACT |
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Monocyte-endothelial cell interactions have
been implicated in the pathogenesis of a number of vascular diseases
that target arterial and aortic endothelium, including atherosclerosis.
Many different adhesion molecules, such as intercellular adhesion
molecule (ICAM)-1, are thought to mediate monocyte binding to
endothelial cells during the development of these diseases. However,
conflicting results have been reported regarding the specific role of
ICAM-1 in these events. In this study, we used a genetic approach to determine the contribution of ICAM-1 in mediating monocyte adhesion to
mouse aortic endothelial cells (MAEC) derived from both wild-type and
ICAM-1/
mice. Treatment of wild-type MAEC with oxidized
low-density lipoprotein significantly induced both WEHI 274.1 and whole
blood monocyte adhesion, whereas similarly treated
ICAM-1
/
MAEC showed a complete inhibition of monocyte
binding. Dose-response treatment with tumor necrosis factor-
also
increased monocyte adhesion to wild-type MAEC, but significant adhesion
was only observed at higher doses for ICAM-1
/
MAEC.
These data demonstrate a crucial role for ICAM-1-mediated monocyte-endothelial cell interactions in response to specific stimuli
involved in inflammatory vascular diseases.
atherosclerosis; oxidized lipids; inflammation; gene targeting; leukocyte; intercellular adhesion molecule
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INTRODUCTION |
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MONOCYTE-ENDOTHELIAL CELL INTERACTIONS are thought to be critical for the initiation and progression of many inflammatory vascular diseases that involve arterial and aortic endothelium, such as atherosclerosis and vasculitis. An early event in atherosclerotic lesion development is the recruitment of monocytes into subendothelial segments of arteries, which ultimately leads to the formation of foam cells (6, 36). Similarly, monocytic infiltration of arteries and arterioles is observed during vasculitic lesion formation in diseases such as Wegener's granulomatosis, polyarteritis nodosa, and giant cell arteritis (15). Many different adhesion molecules are thought to facilitate monocyte-endothelial cell interactions in these diseases, including the selectins, intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM)-1, and the integrin ligand VLA-4 (very late antigen). However, the specific interactions and individual contributions of these adhesion molecules involved in monocyte binding remain to be fully determined.
ICAM-1 is a member of the immunoglobulin superfamily of adhesion
molecules and is expressed on many different cell types including endothelium (10, 41). This adhesion molecule, through
interactions with its 2-integrin ligands LFA-1
(lymphocyte function-associated antigen) and Mac-1, is thought
to play key roles in inflammatory and immune responses by mediating
leukocyte firm adhesion, transendothelial migration, and lymphocyte
costimulation. Several different pieces of experimental evidence
implicate ICAM-1 interactions in monocyte/arterial adhesion events
during the development of atherosclerosis and vasculitic disorders
(15, 36). For example, increased ICAM-1 expression has
been correlated with increased infiltration of monocytes in disease
specimens and in animal models (7, 13, 23, 28, 33, 36,
37). In addition, many of the inflammatory mediators associated
with endothelial cell activation in these diseases, such as oxidized
lipids and cytokines, can significantly increase ICAM-1 expression on
cultured endothelial cell lines (12, 14, 46). Finally,
loss or inhibition of ICAM-1 expression has been reported to decrease
both atherosclerotic and vasculitic lesion formation in animal models
(3, 4, 27, 29, 32). Although these reports suggest
that ICAM-1 may be an important mediator of monocyte adhesion during
these diseases, the examination of monocyte adhesion to
ICAM-1-deficient endothelium has not been determined.
In vitro endothelial model systems have been used to investigate the
contribution of ICAM-1 to monocyte adhesion (19-21,
26). Although it appears from these studies that ICAM-1 is at
least partially involved in monocyte binding in response to
interleukin-1, high glucose, and endotoxin, conflicting reports
exist regarding the role of ICAM-1 in response to other inflammatory
stimuli, such as oxidized low-density lipoproteins (oxLDL) and tumor
necrosis factor (TNF)-
(9, 12, 17, 26, 38, 42). For
example, Erl et al. (9) have shown that Mac-1-ICAM-1
interactions contribute to monocyte adhesion in response to oxLDL,
whereas Shih et al. (39) have reported that ICAM-1 was not
involved in oxLDL-stimulated monocyte binding. These findings may be
due to differences in the experimental reagents used, the source of
endothelial and monocyte cell populations, and the methods used to
inhibit adhesion molecule interactions.
This study employs a genetic approach to specifically examine the role
of ICAM-1 in initiating monocyte adhesion to aortic endothelium in
response to TNF- or oxLDL. Aortic endothelium from normal and
gene-targeted ICAM-1-deficient (ICAM-1
/
) mice were
isolated and cultured, and adhesion assays were performed with the use
of both a monocyte cell line and whole blood monocytes. We report that
monocyte adhesion to ICAM-1
/
mouse aortic endothelial
cells (MAEC) was completely inhibited in response to oxLDL. In
contrast, loss of ICAM-1 resulted in a significant, but incomplete,
attenuation of monocyte binding following TNF-
treatment. These data
clearly demonstrate that ICAM-1 is critical for monocyte adhesion to
aortic endothelium in response to two different inflammatory stimuli
implicated in the development of cardiovascular disease. Moreover,
these findings illustrate that the requirement for ICAM-1-mediated
adhesion can vary depending on the type and strength of the
inflammatory stimulus.
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MATERIALS AND METHODS |
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Mice. Wild-type C57BL/6J mice were obtained from Jackson Laboratory (Bar Harbor, ME). The ICAM-1 mutant mice used in these studies were backcrossed 12 generations onto the C57BL/6J strain background (40).
Endothelial isolation procedure. Endothelial cells were isolated as previously described (16). Isolated cells were plated onto 0.5% gelatin-coated six-well plates in medium containing MCDB-131 (pH 7.2), 10% fetal bovine serum (GIBCO), 1 mg/ml penicillin-streptomycin (GIBCO), 1 µg/ ml hydrocortisone (Sigma), 10 U/ml heparin (Sigma), and 50 µg/ml endothelial mitogen (Biomedical Technologies). Cell passages 3 and 5 were used for these studies with no differences noted between passage numbers.
Monocyte cell culture. The mouse monocyte cell line WEHI 274.1 was purchased from American Type Culture Collection and maintained in suspension culture as previously described (43). Cells were labeled with 1 µM 2',7'-bis-2-carboxyethyl-5-carboxyfluorescein acetoxymethyl ester for adhesion assays (Molecular Probes).
Monocyte adhesion assay.
Endothelial monolayers were treated with 0, 1, 5, 10, or 25 ng/ml
TNF- or 100 µg/ml LDL, which had been oxidized to differing degrees, for 6 h. WEHI 274.1 adhesion was determined as previously reported (14, 16). Whole blood monocyte adhesion assays
were performed as previously described (35). Briefly,
mouse whole blood was diluted 1:10 in Hanks' balanced salt solution
and added to endothelial cell monolayers at 37°C for 15 min.
Nonadherent cells were removed, and endothelial monolayers were washed.
Adherent monocytes were determined by differential staining and
counted. Some assays were also performed with 5 µg/ml of the
ICAM-1-blocking antibody YN1 (11). Increased monocyte
adhesion is reported as a percentage or the amount of normalized
adhesion. Normalized adhesion was used to clearly demonstrate the
differences in monocyte binding in response to YN1.
Isolation and oxidative modification of LDL. Human LDL was isolated from plasma of healthy donors as previously described (30, 31). LDL was oxidatively modified by using copper ions, and the reaction was stopped by the addition of diethylenetriaminepentaacetic acid (50 µM). The degree of oxidative modification of LDL was determined by measuring the relative electrophoretic mobility (REM) using lipogel electrophoresis (Paragon). The specific oxidation products in oxLDL that are responsible for stimulation of monocyte-endothelial cell interactions have been previously shown to reside in a mildly oxidized or minimally modified LDL (2). OxLDL preparations with REM values between ~1.2 and 2.1 were used because these encompass the range in which minimally modified LDL resides.
Statistical analysis.
TNF- or oxLDL-mediated monocyte adhesion data were analyzed by
one-way ANOVA with Bonferroni posttest vs. control. Direct comparison
of monocyte adhesion between endothelial cell types was determined by
using unpaired t-test. All data are expressed as means ± SE.
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RESULTS |
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WEHI 274.1 monocyte adhesion to oxLDL-stimulated mouse aortic
endothelium.
Initial adhesion studies were performed with the mouse monocyte cell
line WEHI 274.1. Both wild-type and ICAM-1/
MAEC were
treated with LDL that had been oxidatively modified (oxLDL) to varying
degrees (Fig. 1). Oxidative modification
was determined by REM, which reflects oxidative damage to the protein component of LDL that directly correlates with formation of oxidized lipids (30). Figure 1 shows that 100 µg/ml oxLDL at both
REM 1.2 and REM 1.6 significantly increased WEHI 274.1 adhesion to wild-type MAEC (11.21 ± 1.86 and 11.61 ± 1.36%).
Importantly, native LDL treatments did not increase WEHI 274.1 adhesion
to ICAM-1
/
or wild-type MAEC (data not shown). Direct
comparison between wild-type and ICAM-1
/
MAEC revealed
a significant overall attenuation of monocyte adhesion for all oxLDL
treatments. These data clearly demonstrate that ICAM-1 is essential for
monocyte adhesion to aortic endothelium in response to oxidized lipids.
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WEHI 274.1 monocyte adhesion to TNF--activated mouse aortic
endothelium.
Figure 2 shows the amount of WEHI 274.1 adhesion to TNF-
-stimulated wild-type or ICAM-1
/
MAEC. Treatment of wild-type MAEC with various doses of TNF-
caused
a significant increase in WEHI 274.1 adhesion (Fig. 2A). Stimulation with 1, 5, 10, and 25 ng/ml of TNF-
caused 22.27 ± 0.54, 35.12 ± 1.59, 38.12 ± 1.53, and 39.2 ± 2.08%
adhesion of WEHI 274.1, respectively. These data demonstrate that
TNF-
stimulates a dose-response increase in WEHI 274.1 adhesion to wild-type MAEC that is maximal at 5 ng/ml TNF-
.
ICAM-1
/
MAEC were also treated with various doses of
TNF-
(Fig. 2B). Doses of 1 and 5 ng/ml TNF-
did show a
trend toward increased WEHI 274.1 adhesion, but this was not
statistically significant compared with 0 ng/ml TNF-
. However,
treatment of ICAM-1
/
MAEC with 10 or 25 ng/ml TNF-
did result in a significant increase in WEHI 274.1 adhesion (17.17 ± 3.44 and 17.87 ± 4.23%, respectively). Direct comparison of
the 5 and 10 ng/ml TNF-
treatments between wild-type and
ICAM-1
/
MAEC showed a significant reduction in the
amount of WEHI 274.1 adhesion to ICAM-1
/
MAEC (Fig.
2C). Adhesion to ICAM-1
/
MAEC was reduced an
average of 72 and 55% in response to 5 and 10 ng/ml TNF-
,
respectively.
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YN1 inhibition of monocyte adhesion.
We next investigated for potential differences in ICAM-1 function on
wild-type endothelium by using the ICAM-1-blocking antibody YN1
(11). Figure 3 shows the
effects of 5 µg/ml YN1 on WEHI 274.1 adhesion after TNF- or oxLDL
treatment. Figure 3A shows that YN1 significantly decreased
monocyte adhesion to TNF-
-stimulated wild-type MAEC by 30%;
however, adhesion was still significantly greater than in unstimulated
endothelium. Treatment of ICAM-1
/
MAEC with YN1 did not
further attenuate WEHI 274.1 adhesion in response to TNF-
(data not
shown) (18). Comparison of TNF-
-mediated WEHI 274.1 adhesion data from ICAM-1 mutant endothelium and wild-type endothelium
treated with YN1 revealed substantial differences in that the
functional lack of ICAM-1 expression further decreased adhesion
compared with YN1 (55% vs. 30%). In contrast, administration of YN1
completely prevented 100 µg/ml oxLDL (REM 2.1)-mediated WEHI 274.1 adhesion to wild-type MAEC (Fig. 3B), paralleling the findings with ICAM-1
/
MAEC.
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Whole blood monocyte adhesion.
Adhesion assays were performed with circulating murine monocytes to
determine whether any specific differences in adhesion mechanisms exist
between continuous monocyte cell lines and peripheral blood monocytes
(34, 35, 43). Figure 4 shows
that whole blood monocyte adhesion to resting ICAM-1/
endothelial cells was significantly reduced compared with wild-type MAEC. TNF-
or oxLDL both significantly increased adhesion of whole
blood monocytes to wild-type MAEC. Dot-blot analysis also revealed an
increase in ICAM-1 protein levels in wild-type MAEC (data not shown).
TNF-
(10 ng/ml) stimulated adhesion to ICAM-1
/
MAEC,
yet monocyte binding was significantly reduced compared with wild-type
MAEC at this dose. Loss of ICAM-1 completely abrogated monocyte
adhesion in response to oxLDL and was not significantly different from
vehicle treatments. These data confirm results obtained with WEHI 274.1 monocytes and further demonstrate that ICAM-1 is important for monocyte
adhesion to oxLDL-or TNF-
-stimulated endothelial cells.
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DISCUSSION |
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We used a genetic approach to specifically examine the molecular
interactions involved in monocyte adhesion to aortic endothelium. This
approach has several advantages in that it allows analysis of primary
endothelium from tissues directly involved in atherosclerosis and
several vasculitic diseases, eliminates the requirements for monoclonal antibodies or other inhibitors, and allows for adhesion studies of specific leukocyte populations. Using this system, we have
previously shown that basal WEHI 274.1 monocyte adhesion is
significantly greater to wild-type MAEC compared with
ICAM-1/
MAEC (16). Here we have
demonstrated further that ICAM-1 plays a major role in mediating
monocyte adhesion to either oxLDL- or TNF-
-stimulated endothelium.
Oxidized lipids have been reported to increase adhesion molecule
expression, including ICAM-1 on aortic endothelial cells, contributing
to atherosclerotic plaque formation (36). Moreover, specific oxidized lipid products can stimulate monocyte-endothelial cell interactions in vitro (44, 45). We found that
stimulation of wild-type MAEC with oxLDL induced a significant increase
in WEHI 274.1 and whole blood monocyte adhesion that was absent in ICAM-1/
MAEC. These observations are in contrast to
previously reported investigations of monocyte adhesion to human
umbilical vein endothelial cells or human aortic endothelium (9,
17, 25, 39). In these studies, ICAM-1 was shown to have a
minimal role or was not involved in monocyte adhesion in response to
oxidized lipid preparations. These differences may be due to the amount
or degree of oxidized lipids used to stimulate endothelial cells and
the methods used to inhibit monocyte adhesion. It is also possible that
ICAM-1 may act as a central adhesion molecule to facilitate other
adhesive interactions and that the genetic loss of ICAM-1 affects the
efficiency or ability of other adhesion pathways. Nonetheless, our data
clearly demonstrate that endothelial ICAM-1 is critical for monocyte
adhesion in response to oxLDL and further implicates this adhesion
molecule in monocyte-endothelial cell interactions during the
initiation and progression of atherosclerosis.
TNF- is widely recognized as a powerful cytokine involved in
stimulating monocyte adhesion in many inflammatory vascular diseases
(15). We observed that TNF-
stimulated a dose-response increase in monocyte adhesion to wild-type MAEC, whereas only higher
concentrations of TNF-
(10 and 25 ng/ml) induced significant adhesion to ICAM-1
/
MAEC. This finding suggests that
monocyte adhesion in response to lower doses of TNF-
may be largely
ICAM-1 dependent, whereas higher concentrations may stimulate
expression of other adhesion molecules. Other adhesive interactions
that could be involved include VLA-4/VCAM-1, VLA-4/fibronectin (CS-1),
or E-selectin. VCAM-1 and E-selectin are both upregulated in response
to TNF-
and have been previously shown to participate in
monocyte-endothelial cell interactions (3, 14, 24).
Further examination of these and other adhesion molecules is necessary
to fully understand ICAM-1-independent mechanisms of monocyte adhesion.
We also compared the use of blocking monoclonal antibodies to
gene-targeted loss of ICAM-1 in inhibiting monocyte adhesion in
response to inflammatory stimuli. We have previously reported that
coincubation of wild-type MAEC with the ICAM-1-blocking antibody YN1
significantly reduced basal adhesion of WEHI 274.1 monocytes and did
not further reduce basal monocyte binding to ICAM-1/
MAEC (16). Treatment of TNF-
-stimulated wild-type MAEC
with YN1 significantly attenuated monocyte adhesion (30%); however, this effect was not as large as that observed using
ICAM-1
/
MAEC (55%). This observation may result from
many factors, such as incomplete blocking of all ICAM-1 molecules,
competitive inhibition of YN1 by soluble ICAM-1, intracellular
processing of the antibody by the endothelium or monocytes (through Fc
receptor binding), or through the inability of blocking antibodies to
similarly influence intracellular signaling pathways mediated by
endothelial cell adhesion molecules (e.g., immunoglobulin superfamily
members) (1, 22). Although it is not certain as to which
of these explanations is responsible, these data clearly demonstrate
that the ICAM-1
/
MAEC provide a more direct,
unambiguous method of analyzing protein function.
In summary, we have identified a potential molecular mechanism by which
ICAM-1 mutant mice show reduced atherosclerotic and vasculitic lesion
formation. ICAM-1 also may be involved in the recruitment of other
leukocyte populations associated with these diseases, such as T
lymphocytes and dendritic cells. Our data further demonstrate the
differential requirement for ICAM-1 in mediating monocyte adhesion in
response to various inflammatory mediators. These observations suggest
that oxLDL and TNF- stimulate different adhesion pathways, possibly
due to activation of distinct signaling cascades (5,
46).
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ACKNOWLEDGEMENTS |
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We thank Dr. Klaus Ley for the gift of the YN1 antibody.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants HL-10312 (to C. G. Kevil) and AR-46404 (to D. C. Bullard) and American Heart Association Grant 006032B (to R. P. Patel).
Address for reprint requests and other correspondence: D. C. Bullard, Dept. of Genomics and Pathobiology, Univ. of Alabama Birmingham, 1670 Univ. Blvd., Birmingham, AL 35294-0019 (E-mail: pike{at}uab.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4 May 2001; accepted in final form 10 July 2001.
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