© 1999 American Heart Association, Inc.
UltraRapid Communication |
Protective Role of Interleukin-10 in Atherosclerosis
From the Institut National de la Santé et de la Recherche Médicale (Z.M., S.B., M.D., B.E., A.T.), INSERM U141 and IFR "Circulation Lariboisière," Paris; Unité Mixte de Recherche (V.D., F.E., M.F.B., F.B., N.D., D.S.), Centre National de la Recherche Scientifique, Rhône Poulenc Rorer, Vitry-sur-Seine; and INSERM U325 (H.D., C.F., B.S.), Département d'Athérosclérose, Institut Pasteur, Lille, France.
Correspondence to Alain Tedgui, INSERM U141, 41, Bd de la Chapelle, 75475 Paris Cedex 10, France. E-mail alain.tedgui{at}inserm.lrb.ap-hop-paris.fr
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Abstract |
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Abstract—The potential role of anti-inflammatory cytokines in the modulation of the atherosclerotic process remains unknown. Interleukin (IL)-10 has potent deactivating properties in macrophages and T cells and modulates many cellular processes that may interfere with the development and stability of the atherosclerotic plaque. IL-10 is expressed in human atherosclerosis and is associated with decreased signs of inflammation. In the present study, we show that IL-10–deficient C57BL/6J mice fed an atherogenic diet and raised under specific pathogen-free conditions exhibit a significant 3-fold increase in lipid accumulation compared with wild-type mice. Interestingly, the susceptibility of IL-10–deficient mice to atherosclerosis was exceedingly high (30-fold increase) when the mice were housed under conventional conditions. Atherosclerotic lesions of IL-10–deficient mice showed increased T-cell infiltration, abundant interferon-
expression, and decreased
collagen content. In vivo, transfer of murine IL-10 achieved 60%
reduction in lesion size. These results underscore the critical roles
of IL-10 in both atherosclerotic lesion formation and stability.
Moreover, IL-10 appears to be crucial as a protective factor against
the effect of environmental pathogens on
atherosclerosis. The full text of this article is
available at http://www.circresaha.org.
Key Words: interleukin-10 • atherosclerosis • mice • macrophage • lymphocyte • collagen
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Introduction |
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Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by progressive accumulation of lipids, cells (macrophages, T lymphocytes, and smooth muscle cells), and extracellular matrix.1 The inflammatory process is involved throughout the different stages of atherosclerosis.1 Inflammation also plays a major role in atherosclerotic plaque disruption and thrombosis2 3 4 5 and therefore greatly influences the occurrence of acute coronary syndromes and their related mortality.6
During the inflammatory reaction, anti-inflammatory cytokines
are also produced and tend to modulate the inflammatory process.
Whereas a large body of evidence exists to support a role for
proinflammatory cytokines in
atherosclerosis,1 little information is
available regarding the potential role of anti-inflammatory
cytokines in this setting. Interleukin (IL)-10, secreted by
lymphocytes of the Th2 subtype, and also in large amounts by
macrophages, is an anti-inflammatory cytokine with
potent deactivating properties on both macrophages and T
cells.7 8 IL-10 is expressed in early and advanced human
atherosclerotic plaques,9 10 and we have shown recently
that its expression is associated with low levels of both inducible
nitric oxide synthase (iNOS) expression and cell death.10
IL-10 inhibits many cellular processes that could play an important
role in plaque progression, rupture, or thrombosis, including nuclear
factor-
B (NF-B) activation,11 12 metalloproteinase
production,13 tissue factor14 and
cyclooxygenase-215 expression, and
cell death.16 17 Taken together, these data suggest that
IL-10 may greatly influence the local inflammatory process within the
atherosclerotic lesion. To examine the natural in vivo role of IL-10 in
atherosclerosis, IL-10–deficient
(IL-10-/-) C57BL/6J mice were fed an
atherogenic diet, and atherosclerotic lesion size and composition were
evaluated and compared with that in wild-type mice
(IL-10+/+).
Recent seroepidemiological studies have suggested a potential role for various environmental pathogens in the development of atherosclerosis in humans.18 We hypothesized that the individual inflammatory response to common environmental pathogens or pathogen products may greatly influence the atherosclerotic process, and that IL-10 may be crucial in the control of this inflammatory response, which ultimately determines the development of atherosclerosis. To examine this issue, mice (IL-10-/- and IL-10+/+) fed an atherogenic diet were housed under specific pathogen-free (SPF) or conventional (CONV) conditions. Furthermore, we evaluated the protective effect of in vivo transfection of murine IL-10 cDNA in IL-10-/- mice.
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Materials and Methods |
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Mice
Female C57BL/6J IL-10-/- mice and IL-10+/+ mice were obtained from Jackson Laboratory (Bar Harbor, Maine) at 7 to 8 weeks of age and placed on an atherogenic diet for 16 weeks. The atherogenic diet was obtained by the addition of 15% cacao butter, 1.25% cholesterol, and 0.5% sodium cholate to the standard chow diet, which contained 3% fat (UAR). Mice were kept in accordance with standard animal care requirements, housed 4 to 5 per cage, and maintained on a 12-hour light-dark cycle. Water and food were given ad libitum. The mice analyzed were housed under either SPF or CONV conditions.
Morphometric Analysis
After 8 or 16 weeks on the atherogenic diet, mice were killed by
ether overdose, and the basal half of the ventricles and the ascending
aorta were removed, embedded in OCT compound (Tissue-Tek), frozen in
isopentane, and stored at -70°C until processing for
analysis of lipid accumulation in the aortic sinus. Serial
10-µm sections of the aortic sinus with valves (60 to 80 per mouse)
were cut on a cryostat. Of every three sections, one was kept for
immunohistological analysis and collagen
detection. The others were stained with Sudan IV to detect lipid
deposition. The sampling method for calculation of the mean lesion area
per section per animal has been previously described in
detail.19
Collagen fibers were stained with Sirius red. Morphometric analysis was performed with an automated image processor (NS 15000, Microvision) as previously described.20 The lesion collagen content was determined by measuring the relative area/density in 12 contiguous fields in each Sirius red–stained section.
Protein and Lipoprotein Analysis
Cholesterol was measured with a commercially
available kit (Boehringer-Mannheim). Cholesterol in
plasma lipoproteins was assayed after analytical gel filtration
chromatography, with a Superose 6 HR 10/30 column
(Pharmacia). Plasma levels of apoA-I and apoA-II were determined by
immunonephelometric assay.
Immunohistochemical Studies
Frozen sections were incubated with 1:50 normal goat or horse
serum for 30 minutes at room temperature, washed once in PBS, then
incubated with either a primary rat monoclonal antibody against mouse
macrophages, clone MOMA-2 (BioSource International), a primary
rabbit anti-CD3 antibody (DAKO), a primary rat monoclonal antibody
against mouse interferon gamma (IFN-) (BioSource International), or
a primary goat polyclonal antibody against mouse IL-10 (Pharmingen).
Immunostains were visualized after incubation with the
corresponding preadsorbed secondary biotinylated antibodies (Vector
Laboratories) and the use of avidin-biotin horseradish peroxidase
(brown staining) visualization systems (Vectastain ABC kit) (Vector
Laboratories). Irrelevant IgGs were used for negative controls. At
least four sections per animal were analyzed for each
immunostaining. Morphometric analysis was
performed as described above.
Systemic Delivery of Murine IL-10 by Intramuscular Injection of
Expression Plasmid DNA
To assess the effects of IL-10 supplementation on lesion
development, eight IL-10-/- mice were injected
at day 0 and day 30 with the IL-10 expression plasmid, pCor-IL-10 and
six with the control empty plasmid. Murine IL-10 cDNA was cloned into
pCor backbone21 under the control of the cytomegalovirus
promoter (nucleotides -522/+72) and upstream of the simian
virus 40 late polyA signal to generate pXL3458. Control plasmid was a
similar construct devoid of therapeutic cDNA. The IL-10 or control
expression plasmid (15 µg) was injected into both tibial cranial
muscles of the anesthetized mouse as previously
described.22 Briefly, transcutaneous electric pulses (8
square-wave electric pulses of 200 V/cm, 20 ms each, at 2 Hz) were
delivered by a PS-15 electropulsator (Jouan) using two stainless steel
plate electrodes placed 4.2 to 5.3 mm apart, at each side of the
leg. Mice were placed on the atherogenic diet for 8 weeks and were
housed under CONV conditions. In a pilot study in C57BL/6 mice, we
determined the time course of IL-10 plasma levels after intramuscular
administration of the IL-10 plasmid, using an immunoassay kit for the
quantitative detection of murine IL-10 (Cytoscreen, BioSource
International). Given that circulating levels of IL-10 were found
detectable up to day 21, in vivo transfections in
IL-10-/- mice were repeated at day 30 to ensure
long-term IL-10 production.
Statistical Analysis
The effects of genotype and environmental conditions on
lesion area and lipoprotein and apolipoprotein data were determined by
2-way ANOVA. Multiple comparisons were performed using Bonferroni's
method. Simple regression analysis was performed to
analyze the relation between lesion area and HDL
cholesterol in IL-10-/- mice.
Morphometric data were compared using a t test. Data are
expressed as mean±SEM. A value of P<0.05 was considered to
be statistically significant.
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Results |
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After 16 weeks on the atherogenic diet, animal weights were not different between the various groups (Table 1
). After this period, total
plasma cholesterol did not differ between
IL-10-/- and IL-10+/+
mice whether they were housed under SPF or CONV conditions (Table 1).
However, IL-10+/+ mice raised under
SPF conditions showed higher total cholesterol levels than
those raised under CONV conditions (P<0.01; Table 1).
HDL cholesterol levels were significantly lower
in IL-10-/- than in
IL-10+/+ mice, regardless of the environmental
condition (P<0.0001), but were not significantly different
in IL-10-/- mice housed under SPF or CONV
conditions (Table 1).
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Atheromatous Lesions in IL-10-/-
Mice
After 16 weeks on the atherogenic diet,
IL-10-/- SPF mice showed a significant 3-fold
increase in atherosclerotic lesion area in the aortic sinus compared
with IL-10+/+ SPF mice (P<0.001;
Table 2, Figures 1A and 1B). This finding
underscores the natural protective role of IL-10 against diet-induced
atherosclerosis.
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Interestingly, the susceptibility of IL-10-/-
mice to atherosclerosis was exceedingly high in the
mice raised under CONV conditions (30-fold increase in lesion size
compared with IL-10 (P<0.0001; Table 2
, Figures
1C and 1D). Lesion development in
IL-10+/+ mice did not increase in the mice housed
under CONV conditions and was even lower than that observed under SPF
conditions, which was likely due to lower levels of plasma
cholesterol (Tables 1 and 2). However, lesion
area was 4.5-fold higher in IL-10-/- CONV than
in IL-10-/- SPF mice (P<0.0001;
Table 2, Figures 1B and 1D). Two-way ANOVA
confirmed that IL-10 and environmental conditions (SPF or CONV)
significantly affected the size of the arterial lesions
(P<0.0001 for IL-10 and P<0.0001 for
environment), with a significant interaction between the two factors
(P<0.0001). Although HDL cholesterol levels
were lower in IL-10-/- than in
IL-10+/+ mice (Table 1), there was no
correlation between HDL levels and the size of the lesions in
IL-10-/- mice. Moreover,
IL-10-/- mice housed under CONV conditions had
much larger lesions than those raised under SPF conditions with
comparable HDL levels.
Plaque Composition in IL-10-/- Mice
Arterial lesions of IL-10-/-
mice evolved into advanced atheromatous lesions and
frequently contained a central acellular lipid core.
Immunohistochemical analysis showed that the surface area
occupied by macrophages (MOMA-2 staining) in the aortic sinus
was proportional to the size of the atherosclerotic lesion and was
significantly higher in IL-10-/- than in
IL-10+/+ mice (190 364±14 466 versus
6038±707 µm2, respectively,
P<0.0001). However, the percentage of lesion
cross-sectional area occupied by macrophages was not different
between the two groups (58.6±4.5% versus 56.3±6.6% of lesion
cross-sectional area in IL-10-/- and
IL-10+/+ mice, respectively; Figure 2). Interestingly, the number of
CD3-positive lymphocytes per lesion cross-sectional area was 2.5-fold
higher in IL-10-/- than in
IL-10+/+ mice (313.2±50.8 versus 126.3±41.2 T
cells/mm2, respectively, P<0.01;
Figure 2). High levels of IFN- expression were found in
lesions of IL-10-/- mice (17.2±3.2% of lesion
area), whereas IFN- expression was barely detectable in
IL-10+/+ mice (0.19±0.06% of lesion area,
P=0.0004; Figure 3). However,
these mice expressed detectable levels of IL-10 (9.7±2.6% of lesion
area) compared with IL-10-/- mice in which
IL-10 was undetectable (P=0.0045; Figure 4). Enhanced expression of iNOS was also
detected in lesions from IL-10-/- mice (data
not shown). These findings indicate that atheromatous
lesions of IL-10-/- mice are characterized by
an increased infiltration of activated T cells with a Th1
cytokine profile accompanied by an exaggerated proinflammatory
response.
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IL-10 and IFN- may regulate differently various enzymes and proteins
implicated in extracellular matrix remodeling,13 15 23 24
which may have an important impact on plaque collagen content and
stability. Therefore, we determined the collagen content in
atheromatous lesions of IL-10+/+
and IL-10-/- mice. Because small early lesions
of IL-10+/+ mice consist of pure
macrophage accumulation, only relatively large lesions were
examined for the presence of collagen by staining with Sirius red.
Despite the very large size of atheromatous lesions in
IL-10-/- mice, there was a very low collagen
accumulation in the lesions (Figure 5).
In contrast, substantial collagen accumulation could be detected in
relatively large lesions from IL-10+/+ mice
(Figure 5). This was confirmed by a quantitative
analysis of collagen content showing a marked decrease in
collagen content in IL-10-/- mice lesions
(4.37±1.06% versus 19.79±5.02% in IL-10-/-
mice, n=8, and IL-10+/+ mice, n=4, respectively,
P<0.002; Figure 5). Absence of IL-10 appears to
favor the development of large atheromatous plaques
characterized by an exaggerated proinflammatory response and a reduced
collagen content, which may greatly increase the plaque susceptibility
to rupture.
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In Vivo Injection of Murine IL-10 Expression Plasmid DNA in
IL-10-/- Mice
IL-10–encoding (or control) plasmid was transferred to muscle
cells using a highly efficient electrotransfer procedure recently
developed.22 In a pilot study in C57BL/6 mice (n=4), we
found that peripheral circulating levels of IL-10 peaked at
day 4 (1101±247 pg/mL) and remained detectable up to day 21 (68±24
pg/mL), and were 458±116 pg/mL and 102±30 pg/mL at day 7 and day 14,
respectively. Therefore, to ensure long-term IL-10 production,
the IL-10 or control expression plasmid (15 µg) was
electrotransferred into both tibial cranial muscles of mice at day 0
and day 30 on the atherogenic diet. This led to high plasma values of
circulating IL-10 (1146.94±131.38 pg/mL) 4 days after the first
electrotransfer, similar to those found in the pilot study in C57BL/6
mice. After 8 weeks on the atherogenic diet, substantial fatty lesions
were observed in the aortic sinus of IL-10-/-
mice injected with the control expression plasmid (pCor) and housed
under CONV conditions (47 963±10 899
µm2. In vivo intramuscular injection with the
pCor-IL-10 expression plasmid resulted in a marked reduction in fatty
lesion development (18 069±1565 µm2,
P<0.01).
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Discussion |
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Signs of chronic inflammation are present throughout the different stages of atherosclerosis, and various pathophysiological mechanisms have been identified that may influence the development and progression of the lesions.1 However, although a large body of evidence is accumulating on the destructive role of proinflammatory cytokines in atherosclerosis,1 little is known regarding the role of the anti-inflammatory component of the reaction. This information may be helpful because it may improve our understanding of the pathophysiology of atherosclerosis and may open the way for the identification of novel therapeutic strategies to combat this common and fatal disease.
Among the anti-inflammatory cytokines, we considered IL-10 as a
cytokine with potentially potent antiatherosclerotic effects.
IL-10 is produced by various inflammatory cells, especially
macrophages, and could therefore be produced locally within the
atherosclerotic lesion. Because IL-10 has deactivating effects on
macrophages and T cells,7 8 it could play a
significant role in the modulation of the local inflammatory reaction.
Also, previous studies have shown that IL-10 modulates several cellular
pathways that may play an important role in the development and
progression of atherosclerosis, including NF-B
activation,11 12 tissue factor14 and
cyclooxygenase-215 expression,
metalloproteinase production,13 and cell
death.16 17 Moreover, IL-10 is produced within advanced
human atherosclerotic plaques,9 10 and we have shown
recently that its expression in the plaque is associated with lower
expression of iNOS and decreased cell death.10 Taken
together, these data prompted us to examine the in vivo role of IL-10
in atherosclerosis by using IL-10–deficient mice
generated on the genetic background of the inbred strain C57BL/6, a
strain susceptible to the development of
atherosclerosis when maintained on an atherogenic
diet.25 Our present study demonstrates a protective
role of IL-10 against atherosclerosis because the
absence of this anti-inflammatory cytokine in mice raised under
SPF conditions led to a marked increase in the susceptibility to
diet-induced atherosclerosis.
In conditions of real life, however, animals and humans are exposed to a variety of environmental factors, including common pathogens and pathogen-derived products. Such conditions may affect the individual inflammatory responses. Previous studies have shown that the intestinal inflammation that characterizes IL-10-/- mice is exaggerated in the mice housed under CONV conditions, although no active intestinal infection can be detected.26 Interestingly, recent studies in humans have suggested a link between prior exposure to pathogens and subsequent development of atherosclerosis.18 We therefore investigated atherosclerosis development in IL-10-/- mice fed an atherogenic diet and raised under CONV conditions. Diet-induced atherosclerosis was markedly increased (4.5-fold increase) in these mice compared with that observed in IL-10-/- mice raised under SPF conditions. This marked increase in atherosclerosis occurred in the absence of active infection with known infective pathogens (data not shown) and could not be accounted for by changes in lipoprotein profiles, because total cholesterol and HDL cholesterol levels were not different in IL-10-/- mice raised under SPF or CONV conditions. HDL cholesterol levels were lower in IL-10-/- than in IL-10+/+ mice, which points out to the potential role of the balance between proinflammatory and anti-inflammatory cytokines in HDL metabolism. This may have contributed in part to the higher susceptibility to atherosclerosis in IL-10-/- mice raised under SPF conditions. Previous studies have reported an association between inflammation and decreased HDL cholesterol levels,27 28 but the mechanisms are not well understood, and further studies are required to elucidate this issue.
Interestingly, fatty lesion development did not increase in IL-10+/+ mice housed under CONV conditions. It was even higher under SPF conditions. This unexpected result is probably due to the higher cholesterol levels achieved, for unknown reasons, under SPF conditions. Our results indicate that the interaction between various environmental factors and the arterial wall becomes critical in the atherosclerotic process only when IL-10 is absent. We therefore propose that individual variations in the quality and extent of the inflammatory response to environmental factors (particularly variations related to IL-10 production) may greatly influence the atherosclerotic response of the arterial wall to an atherogenic diet. This hypothesis may be relevant to the situation in humans in whom individual variations in IL-10 production have been documented and may in part be under genetic control.29
Clinical studies in humans have shown that the clinical prognosis
of a patient with atherosclerosis depends only in part
on the size of the lesions.3 4 30 31 It is now widely
accepted that the quality (plaque composition), rather than the size,
of the lesion could be a better indicator of the development of
ischemic events. Indeed, severe clinical manifestations of
atherosclerosis (infarctions of the heart and the
brain) are mainly due to vessel lumen occlusion by a thrombus formed
on contact with a disrupted atherosclerotic
plaque.3 4 Pathological studies have shown that vulnerable
or unstable plaques (ie, plaques prone to rupture or having ruptured)
greatly differ in cell and matrix composition compared with stable
plaques, not prone to rupture.23 32 The vulnerable plaques
are rich in inflammatory cells (as is the case of the
IL-10-/- mice lesions shown in the present
study), contain a thrombogenic lipid core, and are characterized by a
thin fibrous cap with a substantial loss in extracellular
matrix.23 32 Apoptotic cell death contributes to
the formation of the acellular lipid core33 and has been
shown to be an important determinant of plaque
thrombogenicity.34 Decreased collagen synthesis (mediated
in part by IFN-) and increased activity of
macrophage-derived matrix degrading metalloproteinases are
responsible for fibrous cap thinning and fragility.23
Rupture of the fragile fibrous cap exposes the highly thrombogenic
lipid core to the circulating blood and results in occlusive thrombus
formation.1 23 Therefore, collagen content of a given
atherosclerotic lesion is considered to be a good indicator of its
stability. In the present study, we examined the matrix and cell
composition of the arterial lesions in
IL-10-/- and IL-10+/+
mice. Lesions of IL-10-/- mice showed increased
infiltration of inflammatory cells, increased production of
IFN-, and interestingly, a very low percentage of collagen in
comparison with lesions of IL-10+/+ mice. These
findings indicate that the absence of IL-10 favors the development of
atheromatous lesions with major signs of increased
vulnerability.
Finally, we assessed the effects of in vivo transfer of murine IL-10 cDNA on fatty lesion development in IL-10-/- mice. Two in vivo intramuscular electrotransfers of pCor-IL-10 plasmid DNA at a 4-week interval markedly increased peripheral circulating levels of IL-10 and were sufficient to induce a substantial 60% reduction in fatty lesions in the mice housed under CONV conditions and fed an atherogenic diet for 8 weeks. These findings strongly support the hypothesis of a protective role of IL-10 in atherosclerosis. It is likely that increasing the peripheral circulating levels of IL-10 permitted an interaction between IL-10 and the endothelium, which may have decreased its state of activation. Moreover, the high circulating levels of IL-10 may have permitted IL-10 to enter the arterial wall, which may have compensated for the lack of local production of IL-10.
In conclusion, our results demonstrate that the lack of the anti-inflammatory cytokine IL-10 has a profound impact on both the development and the composition of the atherosclerotic lesion and point to a major role for this cytokine in the interaction between common environmental factors and atherosclerosis. Our findings were obtained in a mouse model of atherosclerosis in which C57BL/6 mice were fed cacao butter, cholesterol, and cholate. Wild-type mice fed this diet typically develop fatty streaks but do not develop fibrous plaques. In contrast, apoE null mice and LDL receptor null mice develop not only fatty streaks but also fibrous plaques that are more typical of human atherosclerosis. Although our IL-10 null mice do not develop fibrous plaques, our data still suggest that IL-10 may play a role in atherogenesis in humans. Because exogenous IL-10 reduced the atherosclerosis in our model, therapeutic strategies increasing IL-10 production may reduce the extent or severity of atherosclerosis.
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Acknowledgments |
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This work was supported by Fondation de France and by Assistance Publique-Hôpitaux de Paris. The authors acknowledge the technical contribution of Bénédicte Manse and Claire Saulnier.
Received June 28, 1999; accepted September 13, 1999.
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