© 1999 American Heart Association, Inc.
Vascular Biology |
Interleukin-10 Blocks Atherosclerotic Events In Vitro and In Vivo
From the UCLA Departments of Pathology (L.J.P.O., T.O., J.A.B.) and Medicine (L.J.P.O., C.C.H., M.T., J.A.B., A.I.F.) and the UCLA Molecular Biology Institute (A.H.), Los Angeles, Calif.
Correspondence to Laura J. Pinderski Oslund, MD, Department of Medicine/Division of Cardiology, UCLA Medical Center, 47-123 CHS, 10833 Le Conte Ave, Los Angeles, CA 90095-1679. E-mail loslund{at}ucla.edu
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Abstract |
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Abstract—Atherosclerosis can be viewed in part as an inflammatory disease process and may therefore be susceptible to manipulation of the immune state. Interleukin 10 (IL-10) is an inhibitory cytokine produced by activated lymphocytes and monocytes. These studies present evidence that IL-10 can inhibit minimally oxidized LDL (MM-LDL)–induced monocyte-endothelium interaction as well as inhibit atherosclerotic lesion formation in mice fed an atherosclerotic diet. Pretreatment of human aortic endothelial cells (HAECs) for 18, but not 4, hours with recombinant IL-10 caused a significant decrease in MM-LDL–induced monocyte binding. IL-10 was found to be maximally effective at 10 ng/mL. Transfection of HAECs with adenovirus expressing viral bcrf-1 IL-10 (Ad-vIL-10) in a sense but not antisense orientation completely inhibited the ability of MM-LDL to induce monocyte binding. Similar results were obtained with IL-10 or Ad-vIL-10 in HAECs stimulated with oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC). We have previously shown increases in cAMP associated with MM-LDL activation of endothelial cells. The MM-LDL–induced increase in cAMP levels was not inhibited by preincubation with IL-10. In vivo studies demonstrated that mice with a murine IL-10 transgene under the control of the human IL-2 promoter have decreased lesions versus controls on an atherogenic diet (5433±4008 mm2 versus 13 574±4212 mm2; P<0.05), whereas IL-10 null mice have increased lesions (33 250±9117 mm2; P<0.0001) compared with either controls or IL-10 transgenic mice. These studies suggest an important role for IL-10 in the atherosclerotic disease process.
Key Words: atherosclerosis • interleukin-10 • MM-LDL • monocytes
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Introduction |
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The pathophysiology of atherosclerosis can be approached on the cellular level as a series of inflammatory stimuli and tissue responses.1 2 Although several components of the immune system have been implicated, monocytes stand out as playing a particularly relevant role. Monocytes have been shown to interact with the vessel wall very early in atherogenesis at sites characteristic of subsequent atherosclerotic lesion development.3 Their presence within atherosclerotic lesions leads to elaboration of chemokines, which may attract smooth muscle cells to invade the developing lesion and attract additional monocytes.1 2 Monocytes engulf oxidized lipids within the lesion, elaborating into "foam cells." Later in lesion development, release of macrophage-derived substances such as metalloproteinases versus tissue inhibitors of metalloproteinases may partially regulate the morbid events associated with plaque instability and rupture.4 5 6 7
Oxidized lipoproteins, in particular minimally modified LDL (MM-LDL), have been demonstrated to induce an inflammatory state in endothelial cells.8 MM-LDL and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) can lead to the development of a proinflammatory, activated state that may contribute to the development of recognition, adhesion, and migration of immune cells into areas of vascular tissue, leading to atherosclerotic disease.9 In tissue culture, it has been shown that MM-LDL can activate human aortic endothelial cells (HAECs), leading to monocyte adherence. This increased adherence is due to expression of CS-1 containing fibronectin on the apical surface of HAECs.10 MM-LDL has been documented to cause increased production of monocyte chemotactic protein-1 and macrophage colony–stimulating factor, which can lead to monocyte recruitment, proliferation, and differentiation.9 11 12 Furthermore, MM-LDL can increase levels of intracellular cAMP in rabbit aortic endothelial cells and HAECs. H89, an inhibitor of protein kinase A activity, was shown to inhibit monocyte binding to MM-LDL–treated rabbit aortic endothelial cells.13 The biological activity of MM-LDL has been localized to its oxidized phospholipid components.8 One of the lipids contained within MM-LDL, which appears to account for much of its biological activity, is OxPAPC.14 Therefore, some of our present studies were performed with both MM-LDL and OxPAPC.
In addition to oxidized lipids, a number of cytokines found in
atherosclerotic lesions, including tumor necrosis factor (TNF)-
,
interleukin (IL)-1ß, and interferon-
(IFN-), may also be
regulators of the proinflammatory aspects of
atherogenesis.15 In contrast to these proinflammatory
processes, counterregulatory inhibitory mechanisms, such as
select cytokines, are present in biological systems. One
such inhibitory cytokine is IL-10, which is a
pleiotropic cytokine produced by monocytes, lymphocytes, mast
cells, and keratinocytes.16 17 18 This
cytokine has already been implicated in
atherosclerosis: in situ hybridization studies have
identified this cytokine within human atherosclerotic
lesions,19 20 and highly oxidized LDL has been shown to
increase production of IL-10 in human monocytes.20
Our present studies, therefore, were undertaken to determine the
effect of the inhibitory cytokine IL-10 on the
inflammation that occurs in atherosclerosis.
Furthermore, these studies were conducted both in vitro and in murine
models of atherosclerosis in vivo to determine the
potential modulating impact of IL-10 on this important disease
process.
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Methods |
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Cell Preparation
HAECs were isolated and cultured as previously described.21 22 Cells from the 3rd through 10th passages, at 90% to 100% confluence, were used for experiments. Peripheral blood mononuclear cells were isolated from blood samples of healthy human volunteers by a modified Recalde method.8
Endothelial Adhesion Assay
Monocyte binding to HAECs was carried out as previously
described.8 13 Briefly, HAECs were cultured until
confluent (72 hours) in gelatin-coated 48-well tissue culture plates.
They were then stimulated or treated as described in the various
experiments. The treatment or stimulatory agents were aspirated, and
the HAECs were washed 3 times. Monocytes (contaminated with <10%
lymphocytes), at a concentration of 106/mL in a
final volume of 300 µL, were then added to the wells and incubated
for 15 minutes at 37°C, humidified with 5%
CO2. Nonadherent cells were rinsed off with 2
washes in 0.5 mL EC medium (20% FBS in medium 199; Gibco), and the
cells were fixed in 1% glutaraldehyde. The number of
adherent cells was then determined by inverted phase-contrast
microscopy at x250 magnification and a 10x10-mm grid. The number of
adherent cells was assessed by counting 3 uniformly covered central
fields in 3 identically treated wells. We have previously shown that
binding of unstimulated lymphocytes to either unstimulated or
stimulated HAECs is minimal23 ; thus, lymphocytes
contribute negligibly to the bound cells.
Lipoprotein Preparation
Lipoproteins were isolated and prepared as previously
described.14 24 25
Adenoviral Vectors
Recombinant adenovirus containing ß-galactosidase
(Adßgal) was generously supplied by Robert Meidell, MD, University of
Texas Southwestern Medical Center, Dallas. Recombinant adenoviruses
containing the Epstein-Barr virus bcrf-1 cDNA with IL-10 inserted in
the forward (Ad-vIL-10) and in the reverse (Ad-RvIL-10) orientations
were generously supplied by Arnold Berk, MD, University of
California at Los Angeles. Large-scale preparation of adenovirus was
performed as previously described.26
Infection of HAECs With Recombinant Adenoviruses
Endothelial cells in 48-well plates were
infected with Adßgal at multiplicities of infection (MOIs) of 10 to
500 pfu/cell for 72 hours to determine optimum transfection efficiency.
For these studies, HAECs infected with Adßgal were fixed at room
temperature with 1% glutaraldehyde in PBS for 15
minutes, then rinsed 3 times with PBS. The wells were then incubated
with X-Gal (Gibco-BRL) for 30 minutes at 37°C. For experiments in
which monocyte binding was tested, IL-10 or ß-galactosidase
containing adenoviruses were incubated with HAECs at an MOI of 30 in
48-well dishes for 48 hours. Mononuclear cell adhesion assays were
performed 24 hours later. In separate wells, medium was removed 48
hours after infection for measurement of IL-10 secretion with an ELISA
assay (R&D Systems).
cAMP Measurement
HAECs were cultured in 6-well plates. At 
90% confluence,
wells were pretreated with IL-10 (2 U/mL) for 18 hours. Cells were then
treated with 1 mmol/L isobutyl-1-methylxanthine (IBMX), a
phosphodiesterase inhibitor, for 10 minutes. MM-LDL,
cholera toxin, and IL-10 were then added to the various wells.
After treatment, the cells were rinsed with cold 1x PBS containing
4 mmol/L EDTA. PBS/EDTA (0.5 mL) was then added to each well, and
cells were collected by scraping. The wells were rinsed with a second
aliquot of PBS/EDTA and transferred to the same microfuge tube. The
cells were then microcentrifuged at room temperature for 5
minutes. The supernatant was aspirated off, and 200 µL of boiling
50 mmol/L sodium acetate, pH 5.8, was added. Cells were then
sonicated for 20 seconds. Each sample was boiled in a water bath for 5
minutes and then centrifuged for 3 minutes at high speed to
remove proteins. The supernatant was then transferred to fresh tubes
and stored at -8°C until further use. For cAMP assay, 50 µL of the
supernatant was measured in duplicate as previously described with a
125I-labeled kit from
Amersham.13
IL-10 Transgenic and Null Mouse Models
A transgenic mouse model overexpressing murine IL-10 under the
control of the human IL-2 promoter was constructed as previously
described.17 These mice were serially backcrossed for >6
generations onto a C57BL/6J background. All mice used were congenic on
the C57BL/6J background. Seven wild-type C57BL/6J, 7 IL-10 transgenic,
and 9 IL-10 homozygous null mice (Jackson Laboratory, Bar Harbor, Me)
were housed under specific pathogen–free conditions and fed an
atherogenic diet (15% saturated fat, 1.25% cholesterol,
0.5% cholic acid) for 15 weeks. The animals were then fasted
overnight, blood samples were obtained for lipid
analysis,27 and the animals were euthanized. The
aortas were immediately removed and frozen in OCT medium over dry ice,
then fixed, sectioned, and stained with oil red O.27 28
The atherosclerotic lesions were quantified as previously
described.27 28
Statistical Analysis
All statistical analysis was performed with Student’s
t tests with StatView (Abacus Concepts, Inc). Data are
presented as mean±SD.
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Results |
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IL-10 Inhibits Monocyte Adhesion to HAECs In Vitro
To determine the potential effect of exogenous IL-10 on monocyte adhesion to activated HAECs, a series of in vitro experiments was carried out. Our laboratory has previously published that incubation of HAECs with the oxidized lipids MM-LDL8 or OxPAPC14 leads to an increase in monocyte adhesion. There is an dose-dependent increase in monocyte adherence with increasing MM-LDL concentration, with maximal effect at 250 µg/mL of MM-LDL; Figure 1A
. Incubation of
HAECs with IL-10 alone at a concentration from 10 ng/mL for 4 to 18
hours did not affect monocyte–endothelial cell
interactions, which suggests that IL-10 is not cytotoxic at this
concentration for these time periods (Figure 1B). HAECs
pretreated for 18 hours with IL-10 (10 ng/mL) and then stimulated with
MM-LDL (250 µg/mL) showed a significant decrease in monocyte adhesion
versus MM-LDL–stimulated cells that received no IL-10. In contrast,
pretreatment with IL-10 for 4 hours did not significantly alter the
increased monocyte binding that occurred on MM-LDL stimulation (Figure 1B). Dose-response curves for IL-10 revealed maximum
inhibitory concentration to be 10 ng/mL (Figure 1C);
therefore, this dose was used for the in vitro experiments. Similar
results were obtained with experiments carried out with OxPAPC (125
µg/mL) used as the stimulus in place of MM-LDL (Figure 1D).
Importantly, the IL-10 was always removed by washing before
introduction of the monocytes; therefore, these data represent
an effect on the HAECs and not an effect on the monocytes used for
these adhesion assays.
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Effect of Adenovirus-Mediated Overexpression of IL-10 on Oxidized
Lipoprotein–Induced Monocyte Binding
To further examine the effect of IL-10 on
endothelial cell activation caused by oxidized
lipoproteins, adenoviral experiments were undertaken to overexpress
IL-10 in HAECs. We used an adenovirus overexpressing bcrf-1 viral IL-10
(Ad-vIL-10), which has previously been shown to have fewer
immunostimulatory effects than human IL-10.29 30 31 HAECs
were transfected at an MOI of 30 with Ad-vIL-10 for 72 hours before
stimulation with oxidized lipoproteins. (The level of IL-10
overexpression achieved by Ad-vIL-10 at an MOI of 30 was confirmed by
ELISA and was found to be 4 ng/mL in the cell culture supernatant.
Levels of IL-10 were 0 ng/mL in the cell culture supernatant without
transfection or with control adenovirus expressing ß-galactosidase.)
Transfection of HAECs with Ad-vIL-10 inhibited MM-LDL–induced
monocyte-endothelium interaction (Figure 2). Similarly, adenoviral overexpression
of IL-10 blocked OxPAPC-induced monocyte binding (data not shown). In
both cases, a control adenovirus overexpressing ß-galactosidase did
not block the lipoprotein-induced monocyte adhesion. Thus, we conclude
that the delivery of viral bcrf-1 IL-10 via this vector is comparable
to exogenous delivery of recombinant human IL-10, and these data
indicate that IL-10 expression blocks MM-LDL– and OxPAPC-induced
monocyte adhesion to HAECs.
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IL-10 Does Not Alter cAMP Levels in HAECs
MM-LDL has previously been shown to increase cAMP levels in HAECs.
To determine whether IL-10 exerts its inhibitory effects by
blocking this rise in cAMP, studies were conducted with
MM-LDL–stimulating HAECs, and cAMP levels were measured. IL-10 by
itself does not increase cAMP, nor does it block the MM-LDL–induced
increase in cAMP under identical conditions in which it inhibits the
monocyte binding described above (Figure 3). Therefore, it appears that IL-10 acts
at some point downstream of the rise in cAMP.
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IL-10 Overexpression Reduces Atherosclerotic Lesion Development
in Mice
Studies were conducted using murine models to investigate the
impact of IL-10 on the development of atherosclerotic lesions in vivo.
Three groups of mice were used: wild-type C57BL/6J controls (n=7),
IL-10 transgenic mice (n=7), and IL-10 homozygous null mice (n=9). The
IL-10 transgenic mice express murine IL-10 under the control of the
human IL-2 promoter. T lymphocytes from these IL-10 transgenic mice
overexpress IL-10 2-fold to 4-fold, resulting in a shift of the T
lymphocyte population to a TH2
cytokine–producing phenotype, with decreased IFN-
production.17 All mice were on a C57BL/6J
background. After 15 weeks on the atherogenic diet, the total
cholesterol was not significantly different among wild-type, IL-10
transgenic, and IL-10 null mice. The HDL cholesterol was comparable
between the wild-type and transgenic groups; however, it was
significantly lower in the IL-10 null group
(Table). There was a marked
difference in lesion size among the 3 groups, with the IL-10 transgenic
mice displaying significantly less atherosclerotic lesion formation
than either wild-type or IL-10 null mice. The lesions in the wild-type
and IL-10–deficient animals were fatty-streak lesions with
accumulation of small mononuclear cells and lipid; no fibrous caps were
observed at the time of the study (Figure 4). Aortic lesion formation was reduced
in the IL-10 transgenic mice to a mean of 5433±4008
mm2 versus wild-type controls (13 574±4212
mm2; P<0.05; Figure 5). Conversely, the mice homozygous null
for IL-10 had a marked increase in lesion area (33 250±9117
mm2; P<0.0001; Figure 5).
Comparison of lesion size between IL-10 transgenic and IL-10 null mice
revealed a marked difference in the atherosclerotic disease state
(5433±4008 versus 33 250±9117 mm2;
P<0.0001). Thus, there appears to be a significant and
inversely related effect of IL-10 on the atherosclerotic process in
vivo.
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Discussion |
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IL-10 has been shown to inhibit a broad range of immunological mediating processes.32 The action of this pleiotropic cytokine has been found to be cell-type–specific,33 with activating effects on CD8+ T cells32 contrasting with inhibiting effects on monocytes34 and some T-cell subsets.22 In our experimental system, we have found that IL-10 can inhibit the stimulatory effects of the oxidized lipids MM-LDL and OxPAPC (Figures 1A
and 1B) as well as those of cholera toxin
(data not shown) on HAECs, manifested by an inhibition of monocyte
adhesion after 18 hours of IL-10 pretreatment. We have also
demonstrated that recombinant human IL-10 and viral bcrf-1 IL-10 are
both able to achieve this effect. The lengthy pretreatment necessary in
our studies for the inhibitory effect contrasts markedly
with the ability of IL-10 to immediately inhibit
lipopolysaccharide or TNF- activation of
monocytes.34 Because of the length of
endothelial pretreatment required, it is likely that
transcriptional or translational processes are involved. Previous work
from our laboratory has shown that MM-LDL exerts its effects by
initiating an increase in intracellular cAMP.35 We
therefore examined cAMP levels in the presence of IL-10 after
stimulation with MM-LDL (Figure 3) or cholera toxin (data not
shown) and found them to be elevated to levels equivalent to those in
cells identically stimulated but not treated with IL-10. This study
suggests that IL-10 acts downstream of the MM-LDL–mediated increase in
cAMP. IL-10 has been documented to play an important role in inflammatory disease processes in mice. IL-10–deficient mice spontaneously develop a severe form of enterocolitis.16 36 Adoptive transfer of CD45RBhi CD4+ T cells from IL-10 transgenic mice, however, is able to suppress inflammatory colitis development in SCID mice under conditions that would normally cause this form of intestinal inflammation.17 Recombinant inbred BALB/c mice challenged with the intracellular pathogen Chlamydia produce higher levels of IL-10 than do C57BL/6J mice. BALB/c mice subsequently mount a less aggressive inflammatory response and consequently succumb to this infection in greater numbers than an identically treated C57BL/6J group.37 IL-10–deficient mice infected with Chlamydia in sublethal doses develop less granulomatous formation than wild-type mice.38
On the basis of these studies in mice and our results in HAECs in
culture, we next examined the effect of IL-10 on
atherosclerosis in mice. In both IL-10 transgenic and
null mutation mouse models, we investigated the effect of
overproduction compared with normal or absent
production of this inhibitory cytokine on
the development of atherosclerotic lesions with the mice on an
atherogenic diet. We found that IL-10 was able to significantly reduce
the development of atherosclerosis in the mice studied
(Figures 4 and 5) without affecting total plasma
cholesterol. Although HDL cholesterol was not different between
wild-type and transgenic mice, we cannot exclude the possible role the
reduced HDL levels might have played in the IL-10 null mice
(Table). IL-10 null mice had the largest amount of lesion
burden, which decreased in wild-type mice and decreased further in mice
transgenic for IL-10. Although we did not measure the levels of IL-10
in our mice, previous studies have shown that IL-10 is not detectably
increased in the circulating plasma of the IL-10 transgenic mice at 4
weeks of age.17 This study suggests that in the transgenic
mice in which IL-10 is under control of the human IL-2 promoter, IL-10
is increased at the level of the individual lymphocytes. This decrease
in the fatty-streak formation in the IL-10 transgenic group may be
important because of the still unresolved controversy concerning the
role of lymphocytes in atherosclerosis. Several
conflicting studies argue for or against the relevance of T lymphocytes
in the development of atherosclerosis. For instance,
the finding that SCID and RAG-2–deficient mice are still able to
achieve significant levels of atherosclerosis despite
not having lymphocytes39 40 41 appears to be in contrast to
other studies that demonstrate early infiltration and activation of
lymphocytes within atherosclerotic lesions.5 7 42 43 44
Other studies demonstrate a key role for TH1
cytokines, such as IL-1245 or
IFN-,46 in atherogenesis. A compelling study performed
in apolipoprotein E–deficient mice revealed a striking immunological
shift from a predominantly TH1 to a
TH2 phenotype with the stress of
high-cholesterol feeding, as evidenced by immunoglobulin
subclasses and cytokine production.47
Our data with transgenic mice are consistent with a role for lymphocytes in atherogenesis. Whether the decreased atherosclerotic lesion formation in our studies is a direct effect of the lymphocytes themselves or a secondary effect of the lymphocyte IL-10 or the lymphocyte subpopulation on monocytes, endothelial cells, or other cells is not addressed in our in vivo studies. Our data nevertheless strongly support the role of IL-10 in atherosclerosis. Further work focused on this cytokine may reveal important mechanisms in the pathogenesis of atherosclerosis.
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After this manuscript was accepted for publication, a manuscript appeared displaying similar findings for IL-10–deficient mice fed an atherogenic diet. (Mallet et al, Circ Res. 1999;85:e17–e24).
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Acknowledgments |
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This work was supported by National Institutes of Health grant HL-30568 and the Laubisch Fund. Dr Pinderski Oslund is supported by NIH UCLA Cardiovascular Scientist Training Program grant T32-HL-07895. Dr Fyfe was also supported by the Medical Research Council of Canada. The authors wish to acknowledge Cynthia M. Harper for her technical expertise and assistance and thank Robert S. Meidell for his generous advice and support with the adenoviral vectors. We also wish to thank Arnold Berk and Lily Wu for generously providing the Ad-vIL-10 virus.
Received March 24, 1999; accepted July 19, 1999.
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