Pro - and Anti-Inflammatory Cytokine Networks

International Scholarly Research Network
ISRN Vascular Medicine

Volume 2012, Article ID 987629, 17 pages
doi:10.5402/2012/987629
Review Article
Pro- and Anti-Inflammatory Cytokine
Networks in Atherosclerosis
Michael V. Autieri
Department of Physiology, Independence Blue Cross Cardiovascular Research Center and Sol Sherry Thrombosis Research Center,
Temple University School of Medicine, Room 1050, MERB, 3500 North Broad Street, Philadelphia, PA 19140, USA
Correspondence should be addressed to Michael V. Autieri, mautieri@temple.edu
Received 11 October 2012; Accepted 31 October 2012
Academic Editors: D. Guidolin, J. Komorowski, and J. E. Nordrehaug
Copyright 2012 Michael V. Autieri. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Despite advances in prevention and treatment, atherosclerotic vascular disease continues to account for significant morbidity,
mortality, and economic burden in the western world. Our current understanding of this disease presents atherosclerosis as a
chronic inflammatory process involving multiple cell types in various stages of activation, apoptosis, and necrosis. These cells
include monocyte/macrophage, dendritic cells, lymphocytes, endothelial cells, and vascular smooth muscle cells. Activation of
these cells and their processes is initiated and sustained by a complex network of soluble factors termed cytokines. Cytokines
are produced and recognized by both inflammatory and resident vascular cells, allowing crosstalk between these two systems.
Cytokines also regulate the phenotype of many of these cell types. Recognizing functions of these cytokines and their eects on
cells which populate atherosclerotic plaque is key to uncovering targets of therapeutic intervention. This paper will present recent
studies which describe the cellular protagonists of atherosclerosis and the role they play in formation of atherosclerotic plaque. It
will also describe the cytokines which have been identified as produced by and directly aecting dysfunction of these cells. Because
atherosclerosis is considered an inflammatory condition, emphasis will be placed on inflammatory cytokines and their eects on
atherogenesis. We will conclude with new directions in therapeutic strategies and points of emphasis for future research.
1. Introduction
Cardiovascular disease is the leading cause of death in
the western world, with 1 in 5 deaths annually attributed
to cardiovascular etiology [1]. Vascular diseases, including
coronary heart disease, high blood pressure, and stroke,
account for the majority of all cardiovascular diseases.
Despite aggressive dietary modification, lipid-lowering medications, and other therapies, atherosclerotic vascular disease
continues to account for significant morbidity and mortality
in westernized societies and is increasing worldwide due to
the adoption of western diet and more sedentary lifestyle.
It is a significant medical and socioeconomic problem
contributing to mortality of multiple diseases including
myocardial infarction, stroke, renal failure, and peripheral
vascular disease. It will worsen with an increasing number
of patients with comorbidity such as obesity, metabolic
syndrome, and Type 2 diabetes mellitus; conditions linked
with atherosclerotic vascular disease.
1.1. Background. Atherosclerosis is recognized as a chronic,

progressive, and dynamic disease initiated by an excess of
serum concentrations of low-density lipoprotein leading
to local inflammation of large- and medium-sized arteries [2]. The term atherosclerosis is derived from the
Greek words atheroma meaning soft, or porridge-like,
and skleros meaning hard, and was used to describe
the physical appearance of the intima of arteries by a
London physician in the 18th century. A connection between
diet and atherosclerosis was proposed in the early 20th
century by Russian physician Alexander Ignatowski who
was able to induce atherosclerosis-like lesions in rabbits
with a diet of egg yolk and milk, introducing the notion
that excess dietary lipid is atherogenic. The lipid theory of
atherosclerosis has predominated as a major risk factor for
development of atherosclerosis and has driven most of the
therapeutic approaches to combat this disease. Briefly, this
theory posits that low density lipoprotein (LDL) becomes
modified by oxidization as a normal metabolic consequence,
2
or, in the diabetic patent, LDL is also glycated. Oxidized
lipids, including an excess of dietary lipid, are among the
earliest initiating factors for development of atherosclerosis.
Oxidation of LDL exposes numerous epitopes, and oxLDL
trapped in the artery and retained there by extracellular
matrix acts as an antigenic, proinflammatory compound
[3, 4]. Internalization of LDL results in a series of dramatic
events which drive the cellular atherogenic response. For
example, modified LDL is considered to be chemotactic,
leading to extravasation of inflammatory cells to the site of
lipid deposition. It was noted that cholesterol feeding rapidly
initiated monocyte adherence to the endothelium, leading
Gimbrone and colleagues to propose endothelial dysfunction
as a major cellular event in atherogenesis [5, 6]. One
explanation for increased EC/leukocyte interaction is that
internalization of modified LDL can induce gene expression
of a host of inflammatory genes, including cytokines and cell
adhesion molecules (CAMs). Much of this is mediated by the
transcription factor nuclear factor kappa B (NF-B), a master switch for transactivation of inflammatory genes. NF-B
is a redox-sensitive gene regulatory factor that is activated by
modified LDL internalization. In this way, a vicious circle of
lipid oxidation, LDL internalization, NF-B activation, gene
expression, and leukocyte extravasation is sustained as long
as oxidized lipid is present to drive this process. It is this
inflammatory gene expression and leukocyte recruitment
and extravasation into the artery which gave rise to the
inflammatory hypothesis of atherogenesis proposed by Ross
[7] which espouses the view that immune cell adhesion to
activated, or inflamed endothelium is a key cellular event
in development of atherosclerosis. The reader is directed to
several excellent reviews which focus on atherosclerosis as a
localized vascular inflammatory disease [811].
1.2. Anatomy of an Atherosclerotic Plaque. Atherosclerotic
plaque does not form uniformly throughout the vasculature.
Hemodynamic forces at branch points and bifurcations
manifest as decreased laminar flow and increased turbulence
and are predisposed to atherosclerotic lesions. It is at these
more vulnerable areas of the vasculature that the earliest
recognizable atherosclerotic lesions, termed the fatty streak
forms (Figure 1). These streaks are composed of a loose
aggregation of lipid-laden macrophage which congregate in
the intima and are common and present in most individuals,
including children. Although subclinical, the fatty streak is
the starting point for intermediate lesions. The fibrofatty
lesion is an intermediate structure and consists of several
layers of lipid-engorged, activated macrophage termed foam
cells, which are intermixed with activated vascular smooth
muscle cells (VSMCs) recruited from the media. These
activated VSMC are no longer contractile but synthetic,
and elaborate inflammatory cytokines as well as matrix.
These cytokines act to recruit more VSMCs from the media
and immune cells from the circulation, and the matrix
they synthesize acts to increase retention of atherogenic
lipoproteins and other inflammatory cells, maintaining a
chronic, localized vascular inflammatory lesion. The fibrous
plaque is an advanced lesion of greatest clinical importance. Within the microenvironment of the fibrofatty lesion,

smooth muscle cells migrate, proliferate, and synthesize
proteins which cause the lesion to progressively grow and
occlude the lumen. These advanced plaques have a distinct
and organized structure in which a necrotic core containing
macrophage foam cells and T lymphocytes in various stages
of apoptosis, as well as lipids, and calcium deposits are
covered by a dense cap of fibrous connective tissue consisting
of activated smooth muscle cells, collagen, and other matrix
components. This advanced plaque tends to be nonobstructive as the lesion grows outward. The most clinically harmful
consequence of the advanced plaque is its proclivity to
cause thrombotic occlusions. The most common occlusion
is caused by thrombi that develop from plaque rupture. The
plaques most vulnerable to rupture are those characterized
by thin fibrous caps, as most thrombi result from fracture
of this cap [11]. It is suggested that thin caps correlate with
high levels of the T lymphocyte cytokine interferon gamma
(IFN). IFN inhibits VSMC proliferation and collagen
deposition in the cap, while simultaneously increasing synthesis of matrix degradation enzymes. Thus, the tendency of
a plaque to rupture is associated with the structural integrity
of its cap, which correlates with the inflammatory state of
the lesion. Therefore, one can generalize with the statement
that decreasing inflammation can increase plaque stability,
thus reducing the propensity of clinically devastating plaque
rupture. Accordingly, a better understanding of the cellular
composition of atherosclerotic plaque, along with characterization of cytokines which facilitate communication between
these cells, will allow us to develop strategies to attenuate
atherosclerotic vascular disease.
2. Cellular Components and

Mediators of Atherosclerosis
Both immune cells and resident vascular cells participate in
response to oxLDL, manifested by synthesis of inflammatory cytokines and phenotypic modulation. Concordantly,
modulation of each of these cell types potentially represents
a therapeutic modality to attenuate atherosclerosis. The
following sections of this paper will describe the cells and
cytokines which together drive this disease and present
themselves as potential targets of therapeutic modalities.
2.1. Monocyte/Macrophage. Circulating monocytes are the
precursors of macrophage in all tissues. Blood monocytes
migrate from the circulation to tissue in response to signals
from that tissue in response to tissue damage and infection,
where they function to phagocytose damaged cells, foreign
bodies, and toxic molecules, such as oxLDL, among others.
Modified LDL is a biologically active molecule and acts as
a potent monocyte chemoattractant as well as an inhibitor
of resident macrophage motility [4]. Monocytes are the
first inflammatory cells to be recognized in the nascent
plaque, and thus considered preeminent in the process.
Systemic depletion of circulating monocytes by clodronate
significantly reduces plaque formation, pointing to the
preeminence of monocytes in atherogenesis [12]. During the
earliest phases of atherogenesis, blood-derived monocytes

Detectible onset:
3
Years
Two-three decades
Three-four decades
Thin fibrous cap
Cap rupture
Thick fibrous cap
Necrotic core
Normal artery
Intermediate
fibrofatty lesion
Fatty streak
Smooth muscle cell

Endothelial cell
Macrophage
T lymphocyte
Dendritic cell
Apoptotic cell
Foam cell
Lipid droplets
Advanced complicated
fibrous plaque
Figure 1: Anatomy of an atherosclerotic plaque. Hemodynamic forces at vulnerable points are predisposed to atherosclerotic lesions. It is at
these vulnerable areas of the vasculature that fatty streaks, the earliest recognizable atherosclerotic lesions, form. These streaks are composed
of macrophage which collect in the intima and are present in most individuals, including children. Fatty streaks are subclinical, but are the
starting point for intermediate fibrofatty lesions. The intermediate fibrofatty lesion consists of several layers of lipid-engorged macrophage
termed foam cells, which are intermixed with activated VSMCs which migrate from the media. Both cell types synthesize cytokines, which
recruit more VSMCs from the media and immune cells from the circulation, maintaining a chronic, localized vascular inflammatory
environment, leading to lesion growth. The fibrous plaque is an advanced lesion of greatest clinical importance and has an organized
structure in which a necrotic core containing macrophage foam cells, dendritic cells, and T lymphocytes in various stages of apoptosis, as
well as lipid deposits are covered by a dense cap of fibrous connective tissue consisting of activated smooth muscle cells, collagen, and other
matrix components. Outward remodeling is a hallmark of this lesion, which helps maintain lumen diameter, but advanced plaques are the
most clinically dangerous because of their vulnerability to rupture. Vulnerable plaques are those characterized by thin fibrous caps, and most
thrombi result from fracture of this cap. The tendency of a plaque to rupture is associated with the structural integrity of its cap. The most
clinically harmful consequences of the advanced plaque is its proclivity to cause thrombotic occlusions. Thin caps tend to correlate with high
levels of IFN, which inhibits VSMC proliferation and collagen deposition in the cap, while simultaneously increasing synthesis of matrix
degradation enzymes. Cellular constituents of an atherosclerotic lesion. The microenvironment of the atherosclerotic lesion is a dynamic
gathering of resident vascular and infiltrating inflammatory cells. These cells include endothelial, vascular smooth muscle, T lymphocyte,
monocyte, macrophage, macrophage foam cells, and dendritic cells. Cytokines produced by both resident vascular and infiltrating immune
cells generate a complex milieu consisting of multiple cytokines which provides the driving mechanism for continued localized inflammation
and progression of the atherosclerotic plaque.
home to the intima and subintima followed by transmigration through the endothelium then extravasate into the
intima and hence dierentiate into the monocyte-derived
macrophage. In the intima they engulf oxLDL through
receptor-mediated process resulting in a series of highly regulated, albeit maladaptive cellular events which drive the cellular atherogenic response. Oxidized LDL induces macrophage
proinflammatory gene expression, including TNF, IL-1,
and IL-6 [13, 14] through ligand activation of peroxisome proliferator-activated receptor gamma (PPAR) [15].
Chemokines recruit additional monocytes; in the absence
of chemokines, lesion formation is attenuated [16, 17].
Antigenic modified LDL is internalized by macrophage by
scavenger receptors as part of a protective response of these
cells to sequester modified LDL from the greater circulation.
Macrophage can engulf lipid to the extent that they appear
foamy under microscopy, and lipid laden macrophages
are referred to as foam cells. They are metabolically active
and are a major source of chemokines and proliferative and
inflammatory cytokines and their receptors, which maintain
localized inflammation in the intima by recruitment of normally quiescent VSMC from the media into the intima, and
additional monocytes from the circulation into the media
and subintima. Under particular conditions, macrophage
can emigrate out of the plaque, which is associated with
a decrease in plaque size and regression of atherosclerosis,
pointing to these cells in not only initiation of plaque but
also maintenance and expansion of plaque [18].
2.2. Macrophage Polarization. Macrophages are functionally and phenotypically versatile and demonstrate a high
degree of plasticity in response to a wide range of stimuli.
Macrophages can be classified into phenotypic subsets based
on expression of cell surface molecules, cytokine expression,
and eector function. The intraplaque cytokine milieu dictates macrophage dierentiation into the M1, (proinflammatory), or M2, (reparative) phenotypes. Dierential cytokine
production is a key feature of polarized macrophages. The
M1, or classically activated macrophage, participates in and
4
propagates proinflammatory processes, and expresses TNF,
IL-1, IL-6, IL-12, and other proinflammatory cytokines,
and thus is considered to be pro-atherogenic. The M2,
or alternatively activated macrophage, produces IL-10 and
the cytoprotective protein hemeoxygenase-1 (HO-1) and
tends to dampen inflammation [19]. This M2 pathway
is induced by IL-10, IL-4, and IL-13. M2 macrophage
also secretes EC growth and angiogenic factors such as
vascular endothelial growth factor (VEGF) and participates
in wound repair and neovascularization and are sometimes
referred to as reparative macrophages [1921]. Both M1
and M2 macrophages are present in human lesions, and
macrophage phenotypic polarization correlates with lesion
progression [22]. For example, in ApoE/ mice, M1
macrophage dominated over M2 macrophage with disease
progression. In regression studies, the proportion of M1
macrophage to M2 macrophage is decreased [22]. Altogether,
M2 macrophage, and factors that influence macrophage
polarity to M2 may be considered as antiatherosclerotic.
2.3. Vascular Dendritic Cells. Circulating monocytes enter
tissue and dierentiate into tissue macrophage or dendritic
cells (DCs), which share several surface markers with
macrophage, including CD80 and CD86 [9]. It is thought
that the increase in DC in arterial wall and lesion is from
recruitment of pre-DC from the circulation, likely by homing
to a chemokine gradient. DCs undergo a maturation process
from a circulating DC (pre-DC), into a cell capable of antigen
uptake and presentation to T lymphocytes. There are in
turn multiple DC subtypes based on cell surface molecule
and cytokine expression [23]. Functional, antigen-presenting
DCs have extended, dendritic-like cytoplasmic extensions,
and are phenotypically similar to Langerhans cells, with a
somewhat characteristic dendritic shape. DC can be found
in the medial-adventitial border in normal human arteries,
but numbers dramatically increase in the intimal, medial,
and adventitial compartments of arteries with atherosclerotic
lesions [24]. DCs are located in close proximity to T
lymphocytes in shoulder regions of human plaque, further
supporting a role for these cells in atherosclerosis [25].
Dendritic cells are strictly defined as antigen presenting
cells which present antigen to nave T lymphocytes. In contrast to macrophage, DCs have a predilection to localization
and homing to secondary T-cell-rich lymphoid organs where
they interact with T cells [26], and thus are suggested to
represent a link between the innate and adaptive immune
arms of the immune system [27]. Some studies suggest
that oxLDL promotes DC activation and maturation, and
local lymph nodes do contain oxLDL-reactive T cells [28].
Considering their role as professional APC, it is hypothesized
that DCs engulf and process athero-specific antigens [29].
Once activated, they migrate to local lymph nodes, where
they present these antigens and activate nave T cells, driving
their activation. An important study demonstrated that DC
function, antigen processing and presentation, is enhanced
in the dyslipidemic microenvironment [30], suggesting DC
are lipid-sensitive regulators of adaptive immunity.

2.4. T Lymphocytes. In addition to macrophage, human
atherosclerotic plaque contains approximately 10% T lymphocytes [31, 32]. Studies using Rag- (recombination activating gene-) deficient mice crossed with atherosclerosisprone mice demonstrate that a deficiency in lymphocytes
results in over a 50% reduction in atherosclerotic plaque
[33]. Concordantly, adoptive transfer of CD4+ T cells into
ApoE/ /SCID mice enhances plaque development [34].
Together, these important studies emphasize the importance of adaptive immunity in atherosclerosis and suggest
that despite their limited numbers, T cells have a major
impact on atherogenesis. The overwhelming majority of T
lymphocytes found in human plaque are CD4+ , T helper
(Th1) cells. These are activated and primed by antigen
presentation, possibly from macrophage or DC which have
internalized oxLDL particles, as T cells cloned from human
plaque recognize oxLDL [35]. Like multiple sclerosis, and
rheumatoid arthritis, it has been posited that atherosclerosis
is a Th1 disease [31], and Th1 lymphocytes drive cellmediated immunity and are considered proatherogenic as
they secrete potent proinflammatory interleukins such as IL2, IL-12, and cytokines such as IFN. These soluble factors
not only promote T-cell maturation to Th2 phenotype, but
also act on other cells present in the atherosclerotic lesion
such as macrophage, EC, and VSMC to further promote local
inflammation.
Atherosclerosis is highly influenced by the Th1/Th2
balance, and the interplay between these two phenotypes
determines lesion severity [31, 36]. A tip in the balance of
these seemingly opposing forces toward the Th2 expression
profile has been proposed to have antiatherosclerotic eects.
Th1 and Th2 cells originate from a common precursor
cell (Th0), and the local cytokine microenvironment in
the lesion is thought to determine lineage outcome. A
very small proportion of T lymphocytes in the lesion are
Th2-biased, and Th2 cytokines such as IL-4 and IL-10
are far less abundant in human and mouse atherosclerotic lesions [32, 37]. Th2 lymphocytes participate in the
humoral arm of immunity act on B cells to stimulate
antibody production. They are characterized by synthesis
of anti-inflammatory cytokines, including IL-4, IL-10, and
IL-13 [31]. Importantly, deletion of STAT6, a transcription factor that drives dierentiation to Th2, increases
atherosclerosis in resistant mice [38], underscoring the
antiatherogenic eects of the Th2 arm of adaptive immunity.
T cells which express the FoxP3 (forkhead/winged helix)
transcription factor produce TGF upon activation are
termed T regulatory (T reg) lymphocytes and are found
in human atherosclerotic plaque [39]. Depletion of these
cells increases atherosclerosis, and adaptive transfer of T
reg cells increases plaque stabilization in atherosclerosissusceptible mice, suggesting a protective role for this T-cell
subset [40]. TGF induces synthesis of collagen and other
matrix proteins as well as is anti-inflammatory, making this
an important factor in plaque stabilization. T regulatory cells
are considered potently antiatherogenic, and factors which
generate T reg, and the cytokines they elaborate are currently
the subject of intense study.

2.5. Endothelial Cells (ECs). The vascular endothelium is
structurally distinctive as it consists of a single cell layer
of specialized endothelial cells lining the interior of blood
vessels. Normally functioning endothelium is the key to
vascular homeostasis. The endothelium maintains a nonthrombogenic, nonadherent surface; maintains vascular tone
by synthesis of vascular dilatory and constricting molecules;
acts as a permeability barrier for exchange of substances into
artery wall; regulates lipid modification as it is transported
into the artery wall. Perturbation of any one of these normal
functions leads to atherogenesis. Because it is positioned at
the interface between blood circulation and tissue, ECs are
equipped with specialized structures to quickly respond to
local inflammation and flow disturbances. We will focus on
two major functions of EC as they relate to atherogenesis.
2.5.1. Leukocyte Adherence. The progressive accumulation
of transcytosed lipid within the subendothelium is one of
the earliest observable changes in atherogenesis and occurs
within minutes of hyperlipidemia [41]. OxLDL activate
signaling pathways which often converge on the transcription
factor NF-B, which results in transactivation of multiple
proinflammatory genes, particularly chemokines and cell
adhesion molecules (CAMs), which are proangiogenic [42].
The endothelium is the gatekeeper of leukocyte extravasation, which is a multi-step process including rolling,
attachment, and transmigration of leukocytes through the
endothelium linking vessel walls. Coordinated expression of
chemokines and adhesion molecules is essential to ensure
that the appropriate class of inflammatory cells accumulate
at the lesion for the appropriate length of time [43]. The
repertoire of adhesion molecules expressed by EC is dependent on the local inflammatory milieu. Dyslipidemia induces
expression of selectins and ICAM-1, which initiate recruitment and rolling of leukocytes [44]. Continued stimulation
elicits expression of ICAM-1 and VCAM-1, which facilitate
monocyte adherence by interaction with very late-activation
antigen-4 (VLA-4), the counterreceptor to VCAM-1 on the
surface of monocytes. These adhesion molecules are a tether
for leukocytes to adhere, but also initiate signal transduction
events initiated by CAM perturbation. Several in vivo studies
have demonstrated that reduction of selectin or CAM
expression on vascular EC reduces leukocyte extravasation
and subsequent development of atherosclerosis in these mice
[4548]. Secretion of potent chemoattractants such as IL-8
and MCP-1 generate a chemokine gradient which continues
recruitment and directional migration of inflammatory cells
through the media of the vessel.
2.5.2. Sheer Stress and Mechanotransduction. Because of its
anatomical position as a flow interface, ECs are continuously
exposed to blood fluid shear stresses. It has long been
recognized that atherosclerotic lesions develop preferentially
in areas of disturbed or oscillatory blood flow [49]. Vascular
regions which demonstrate disturbed flow are the aortic
sinus, bifurcations, and curvatures of the renal, coronary,
and carotid arteries, all areas with increased lesion formation.
These are regions where blood is likely to move more slowly
5
with some degree of eddying, and perhaps a back and forth
movement during the cardiac cycle. In contrast, in regions
along nonbranching segments, lesions are rarely found [50].
Because of their membrane expression of PCAM-1 and
integrins, one unique feature of endothelial cells is that
they can act as mechanosensors and mechanotransducers,
and are very sensitive to disturbed blood flow. Recent
work has shown that oscillatory shear stress, or other
nonlaminar flow patterns have profound, proinflammatory
eects on EC at the cytoskeletal and gene expression levels.
For example, low or disturbed flow induces expression
of numerous atherogenic genes including PDGF, MCP-1,
and many CAMs, including ICAM-1 and VCAM-1 [51].
Expression of most of these genes is NF-B-dependent,
which is activated in endothelium in areas of disturbed flow.
In contrast, EC in areas of laminar flow demonstrate antiinflammatory eects, with increased production of nitric
oxide (NO), increased activation of Kruppel-like factor2 (KLF-2). KLF-2 is an anti-inflammatory transcription
factor, which can regulate the transcriptional response to
changes in flow by regulating expression of numerous
genes involved in mechanotransduction. Laminar flow is
sucient to reduce TNF-stimulated expression of VCAM1 on EC, demonstrating the importance of laminar flow in
maintenance of EC homeostasis [52].
2.6. Vascular Smooth Muscle Cell (VSMC). Most studies
focus on the role of EC and inflammatory cells, but
VSMCs play an important, and perhaps unappreciated role
in atherogenesis. The overwhelming majority of cells in
the healthy artery are VSMCs. Smooth muscle cells are
present in atherosclerotic plaque at all stages, and migration, proliferation, and synthesis of extracellular matrix by
activated VSMC contribute to early formation of lesions
through several mechanisms, including secretion of inflammatory cytokines, uptake of oxLDL, and elaboration of
chemokines [53]. Smooth muscle cells are somewhat unique
in that they are capable of two phenotypes, contractile
or synthetic, as illustrated by the response to injury
hypothesis proposed by Ross and Glomset [54].In the
healthy artery, fully dierentiated medial VSMC respond
mainly to vasoconstricting or vasodilatory peptides, and
are normally quiescent. However, VSMCs respond to local
inflammation by expressing numerous genes for cytokines,
matrix proteins, and cell proliferation regulatory proteins,
as well as exhibiting a dedierentiated transcriptome and
phenotype. Perhaps not surprisingly, oxidized phospholipids
induce VSMC phenotypic switch to the synthetic, inflammatory phenotype [55]. Activated VSMCs are capable of
synthesizing many proinflammatory immune modulators
[53, 56, 57] which promulgate autocrine activation of
VSMC and recruit macrophage to the developing lesion.
They also synthesize and respond to these soluble factors
in an autocrine and juxtacrine fashion and migrate from
the media into the intima where they proliferate, and, in
the case of atherosclerosis, form a cellular cap over the
developing lipid core. Through their synthesis of matrix
proteins, VSMCs are largely responsible for maintaining
6
plaque stability, and most discussion of VSMC in the
context of atherosclerosis tends to focus on their role in
cap patency and vulnerability of advanced plaque. Ruptureprone plaques have thin fibrous caps characterized by
relatively few VSMCs. VSMCs synthesize the majority of cap
components consisting of collagens, and matrix; therefore,
VSMCs critically influence cap integrity and consequently,
plaque vulnerability. VSMCs respond to the T lymphocyte
cytokine IFN by not only decreasing synthesis of matrix,
but by increasing synthesis of matrix metalloproteinases
(MMPs), which weaken and degrade the fibrous cap [11,
58]. Regions of MMP expression often colocalize with
hemorrhaged areas, which are also characterized by very
few VSMCs, suggesting that combinations of cytokines in
concert with IFN can lead to SMC apoptosis, or at least
attenuation of VSMC proliferation.
Similar to macrophage, VSMCs possess scavenger receptors for oxLDL including lectin-like receptor (LOX-1)
and CD36. VSMC scavenger receptors internalize modified
oxLDL as ligand, accumulate large amounts of cholesterol
esters, and can become foam cells [53, 59]. These receptors
are also increased in the presence of inflammatory cytokines
such as IL-1 and TNF. Many scavenger receptors can
activate multiple signal transduction cascades and stimulate
VSMC migration and proliferation [53, 60]. These gene
expression activation events activate the mitogen-activated
protein kinase (MAPK) signaling cascade and are Id3-,
NF-B-, JNK- and STAT-dependent [53, 61]. In this way,
VSMC lipid internalization also greatly aects the lipid
content and inflammatory milieu of the atherosclerotic
plaque. Consequently, one therapeutic option would be
regulation of expression or function of these receptors
which would not only decrease uptake of oxidized LDL,
but also reduce signal transduction and maladaptive gene
expression. Importantly, oxLDL is proliferative for cultured VSMC inducing a 10-fold increase in DNA synthesis
[62]. In vivo, this proliferative eect may be mediated
by oxLDL-induced synthesis of VSMC mitogens bFGF
and PDGF from other cells in reactive proximity [62].
oxLDL also stimulates expression of chemokines such as
MCP-1, inflammatory cytokines like TNF, and cell adhesion molecules such as VCAM-1, creating a feed-forward
autocrine loop and enabling paracrine activation of other
cells. In atherosclerotic lesions, VCAM-1-positive VSMCs
have been detected juxtaposed with macrophages, suggesting
that activated synthetic SMC retain inflammatory cells.
The arterial wall can regulate atherosclerosis susceptibility
independent of the immune response [63]. C57B6 mice
are more susceptible to diet-induced plaque formation than
VSMCs isolated from C3H mice, which are somewhat
resistant to plaque formation [64]. Cultured VSMCs isolated
from CH3 mice are more responsive to oxLDL-induced
expression of cytokines and adhesion molecules compared
with VSMC propagated from C57B6 mice. The synthesis of
these studies supports the notion of VSMC as a versatile
inflammatory and structural support cell and advocates
the important role of this cell type at all stages of plaque
development and as a potential target of antiatherosclerotic
therapy.
3. Cytokines, Cellular Communication,

and Atherosclerosis
Vascular inflammation is mediated by numerous cell types
which communicate with each other through a series of
cytokine-receptor-mediated interactions allowing bidirectional crosstalk between resident vascular cells and inflammatory cells [8]. For eective communication to take place,
these disparate cell types evolved a common set of soluble
cytokine ligands and specific membrane receptors allowing
them to transmit their eects into the cell. Most cytokines
initiate a complex and varied repertoire of responses on
their target cells and can initiate advance, and potentially,
resolve atherogenic inflammation. The microenvironment of
the atherosclerotic plaque is a dynamic collection of resident vascular and infiltrating inflammatory cells and their
cytokine products. This complex milieu consists of multiple
cytokines with redundant, pleiotropic, and opposing eects,
and the balance of pro- and anti-inflammatory cytokines
often determines plaque severity and stability. Cells present
in the lesion must interrogate and respond to this multitude
of factors in an appropriate fashion, which together often
result in the development and progression of atherosclerosis.
Thus, our current understanding of the role of any individual
cytokine in this disease should be tempered by the fact
that no cytokine exists in a vacuum. Addition of a single
cytokine to cultured cells, or genetic manipulation of mice,
a one gene at a time cannot accurately reflect the in vivo
scenario. As such, it may be more appropriate to think in
terms of cytokine networks which are temporally expressed
and temporally functional.
3.1. Cytokine Classifications. There are currently six families
of cytokines classified by structure as well as function,
including interleukins (with several subfamilies based on
peptide and receptor homology), interferons (IFNs), tumor
necrosis factor family (TNF), chemokines, growth factors,
and colony-stimulating factors (CSFs) (Table 1). Other
categorization strategies have been utilized, and cytokines
can be classified based on structural homology of their
receptors, in which almost all of the above families of
cytokines can be grouped into class I or class II [65]. We
can also distinguish cytokines by the more broad functional
categorization of their being pro- or anti-inflammatory.
Several anti-inflammatory cytokines have been investigated
in non-atherosclerotic disease models. Considering their
anti-inflammatory activity, it is anticipated that these will
eventually be classified as antiatherosclerotic. Accordingly,
when describing a potential role in atherosclerosis, it may be
most useful to categorize cytokines into the broad functional
categories of pro- and antiatherogenic, or undetermined.
3.2. Cytokine Signaling Networks and Function. As they
can be expressed by cells which also express their receptors, cytokines often signal in an autocrine, paracrine, or
juxtacrine fashion. Most cytokines often act in synergy
with other cytokines [66] and can initiate multiple cellular
processes, often simultaneously. For example, TGF can be
Table 1: Cytokines and their sources. EC: endothelial cell, L: lymphocyte, M: monocyte/macrophage, P: platelet, and SMC: smooth muscle
cell.
Proatherogenic
IL-1
IL-6
IL-8
IL-12
IL-18
IFN
TNF
Antiatherogenic
IL-10
IL-33
TGF
Likely antiatherogenic
IL-4
IL-19
Cell source
Cytokine family
Leukocyte phenotype
Detected in plaque
Primary signaling
M, L, EC, and SMC

M, L, EC, and SMC
M, L, EC, and SMC
M, L
M
M, L, EC, and SMC
M, L, and SMC
IL-1
IL-6
IL-8
IL-6
IL-1
IFN
TNF
+
+
+
+
+
+
+
p38/NF-B
JAK1/STAT3
GPCR/NF-B
JAK2/STAT3
p38/NF-B
JAK1/STAT1,2
p38/NF-B
M, L
M, L
M, L, SMC, and P
IL-10
IL-1
TGF
Th2
Th2
Th2
+
+
+
JAK1/STAT1,3,5
p38/NF-B
SMAD2,3
L
M, L, EC, and SMC
IL-4
IL-10
Th2
Th2
JAK1/STAT5
JAK1/STAT3
mitogenic, drive development, and influence fibrotic gene

expression. They are promiscuous in their use of receptor
subunits and frequently share one or more homodimers or
heterodimers of receptor subunits with other cytokines. For
example, IL-19, IL-20, IL-22, and IL-24 all share receptor
subunits, but display distinct cellular eects [67]. The
observation that several cytokines are synthesized by resident
vascular cells and recognized by immune cells supports the
hypothesis that vascular cells can be considered as part of the
adaptive immune system.
Cytokine engagement of their equivalent receptor initiates a series of intracellular signaling events including
activation of a multitude of kinases and transcription factors
[68]. Proinflammatory cytokines most often lead to activation of nuclear factor (NF-B), a transcription factor which
acts as a master switch for transcription of numerous
genes central for inflammatory responses [69]. These genes
include matrix and matrix degrading enzymes, cytokines
and their receptors, and adhesion molecules which lead to
matrix deposition, fibrinolysis, chemotaxis, and leukocyteendothelial adhesion; all key processes in atherogenesis.
Anti-inflammatory cytokines often dampen the activity of
proinflammatory cytokines by a series of negative feed back
loops mediated by de novo expression of suppressors of
cytokine signaling (SOCS) family of proteins, which bind
to the cytoplasmic tail of cytokine receptors and signaling
intermediates [70].
3.3. Proatherogenic Cytokines. Overall, Th1 interleukins are
much more prevalent in human atherosclerotic lesions
than the Th2 cytokines [32, 71]. Because atherosclerosis
is primarily an inflammatory condition, we will categorize
our focused discussion into pro- and anti-inflammatory
cytokines, with particular attention given to those cytokines
with demonstrated eects on atherosclerosis.
Th1
Th1
Th1
3.3.1. IFN. IFN is expressed by most cell types present

in atherosclerotic plaque including macrophage, T cells, and
VSMC in human, and experimental lesions in mice. The
majority of T cells present in atherosclerotic plaque are Th1positive cells, which produce abundant amounts of IFN.
Macrophage, EC, and VSMC produce IFN in response to
inflammatory stimuli; since IFN is a strong inducer of
the Th1 phenotype, this leads to a propagation of localized
inflammation. IFN signals through the JAK/STAT pathway
and also activates the SMAD signaling complex leading
to inflammatory cytokine production, and in addition to
polarizing T cells to the Th1 phenotype, IFN also induces
macrophage, EC, and VSMC to express proinflammatory
genes (reviewed in [66, 68]). IFN-induced ICAM and
VCAM-1 expression in EC leads to increased extravasation of
circulating T cells, thus increasing the inflammatory burden
in atherosclerotic lesions.
Several direct lines of evidence from animal models indicate that IFN is a potent proatherogenic cytokine. Systemic
intraperitoneal IFN administration promoted atherosclerosis in ApoE/ mice [72]. Concordantly, IFNR/ /ApoE/
double knockout mice display a reduced atherosclerotic
burden compared with controls [73]. Similarly, gene transfer of a secreted IFN receptor decoy in ApoE/ mice
prevented progression of atherosclerotic plaque [73, 74].
There are various modes of action that point to IFN as
a powerful pro-atherosclerotic agent. In addition to Th1
polarization, IFN can reduce cap VSMC proliferation and
collagen deposition, while also inducing MMP expression in
VSMC, leading toward plaque instability and susceptibility
to rupture [73]. Indeed, increased IFN levels are seen
in unstable plaque [75]. IFN can also increase oxidized
lipid uptake and foam cell formation in macrophage and
VSMC. IFN also mediates the pro-atherosclerotic eects
of the proinflammatory cytokine IL-18. Injection of IL-18
increased lesion size in ApoE/ mice [76]; this is inhibited
8
in IFN/ApoE double knockout mice [74]. Together, IFN
can influence plaque progression at multiple levels and is a
potent pro-atherosclerotic cytokine.
3.3.2. TNF. Tumor necrosis factor alpha is a member
of the TNF superfamily which on the basis of sequence,
functional, and structural similarities, currently contains
nineteen distinct cytokines. Canonical TNF signaling is
mediated by p38 MAPK and NF-B. Its induction of other
proinflammatory cytokines has earned TNF the moniker
of master inflammatory cytokine. TNF is a pleiotropic
cytokine with potently proinflammatory eects and can
induce a cascade of proinflammatory gene expression including IL-1, IL-8, MCP-1, ICAM-1, VCAM-1, and MMPs in a
variety of cell types including lymphocytes, macrophage, EC,
and VSMC. Though primarily colocalizing with monocytes
and macrophage, TNF immunoreactivity is found in all
of these cell types in human and experimental atherosclerotic plaque. Similarly, serum TNF levels correlate with
atherosclerotic plaque burden assessed by carotid artery
IVUS, raising the possibility that this cytokine can be used
as a noninvasive biomarker for atherosclerosis development
[77]. Consistent with its eects on CAM expression, TNF
promotes leukocyte/endothelial cell interaction in vivo [78].
Perhaps more clinically relevant, TNF is associated with
plaque rupture as it stimulated production of several MMPs
[79], and more ominously, TNF induces expression of
tissue factor, a thrombogenic protein which plays a role in
plaque rupture [80].
In animal models, TNF/ApoE double knockout mice
have significantly reduced atherosclerotic plaque compared
with controls and reduced inflammatory serum cytokine
levels and reduced CAMs expression [81]. In studies on
ApoE/ mice treated with recombinant soluble TNF p55
receptor, lesion size was reduced [82]. Studies on TNFreceptor-deficient mice surprisingly resulted in increased
plaque burden, but likely because of elevated cholesterol
levels in these mice. Overall, because of its powerful proinflammatory eects on all cell types present in atherosclerotic
lesions, TNF is a potent protagonist of atherosclerosis and
continues to present an attractive target of interventional
therapy.
3.3.3. IL-1. The IL-1 family is composed of four proteins
which share sequence homology: IL-1, IL-1, IL1receptor
antagonist, and IL-18 [83]. IL-1 immunoreactivity is found
in monocyte, macrophage, EC, and VSMC in human and
experimental atherosclerotic plaque, and IL-1 is produced
by macrophage, monocytes, EC, and VSMC. IL-1 is induced
by other proinflammatory stimuli, including TNF, and
is strongly proinflammatory as it initiates expression of
other inflammatory cytokines in multiple cell types [32,
66]. IL-1 signals activate p38 MAPK and converge on
NF-B, thus eliciting expression of cytokines and adhesion
molecules, and are mitogenic for VSMC and EC [84]. IL1 is instrumental in early lesion formation as it increases
leukocyte/EC interactions, thus facilitating extravasation
[85]. Because it can induce leukocyte extravasation into

the developing lesion and also induce cytokine expression
in almost every cell present in the lesion; autocrine and
paracrine IL-1 production not only initiates, but maintains
the local inflammatory milieu. Multiple animal models
demonstrating direct, pro-atherosclerotic eects are reported
for IL-1. Infusion of IL-1 receptor decoy reduced fattystreak area in ApoE/ mice [86]. Similarly, increased lesion
area with marked increase in macrophage infiltrate was
observed in IL-1 receptor/ApoE/ double knockout mice
[87]. IL-1/ApoE double knockout mice showed a 30%
decrease in atherosclerosis [88].
3.3.4. IL-6. IL-6 has potent proinflammatory eects in a
variety of cell types. EC, VSMC, and macrophage all synthesize IL-6. It is expressed in human atherosclerotic plaque and
increased in serum in patients with CAD and unstable angina
and is considered an independent risk factor for coronary
artery disease [66]. IL-6 enhances CAM expression in EC
and VSMC, contributing to extravasation of leukocytes into
the developing atherosclerotic lesion. IL-6 signals through
the JAK/STAT family of signal transducers and is mitogenic
for VSMC. A direct role for IL-6 in atherogenesis has
been established as systemic injection of ApoE/ with
recombinant IL-6 resulted in significantly increased plaque
[89]. Unexpectedly, lesion size was increased in IL-6/ApoE
double knockout mice [90]. Potential mechanisms for
this counterintuitive result was an unanticipated increased
expression of IL-10, and increased IL-1R and TNF receptors, which were assumed to neutralize bioavailability of
these potent proinflammatory mediators. In summary, while
a potent proinflammatory cytokine, IL-6 can have complex
and somewhat confounding antiatherosclerotic side eects.
3.3.5. IL-8. IL-8 is a potent chemoattractant for leukocytes
and other cell types including VSMC [91]. IL-8 is detected in
human atherosclerotic plaque, and serum levels are increased
in patients with hypercholesterolemia and unstable angina
[92]. IL-8 expression is induced in macrophage by oxLDL
and in EC and VSMC when challenged with TNF and
IL-1. As a potent chemoattractant, IL-8 is an important
pro-atherogenic cytokine as it enhances lesion formation by
expediting leukocyte extravasation and EC adhesiveness [93].
IL-8 can contribute to plaque instability by inhibition of
TIMP-1 (tissue inhibitor of metalloproteinase) expression.
In animal models, IL-8 pro-atherogenic eects are likely
mediated primarily by leukocytes, as transplantation of
IL-8/ bone marrow into LDLR/ recipients results in less
atherosclerosis compared to IL-8+/+ bone marrow [94].
3.3.6. IL-12. IL-12 (p70) is composed of the p35/p40
heterodimeric complex and plays an important role in
lymphocyte Th1 dierentiation. IL-12 is detected in
human atherosclerotic plaques and is proposed to be proatherosclerotic in humans as it enhances T-cell recruitment
to the lesion [95, 96]. IL-12 signals through the JAK/STAT
complex and induces Th1-polarized cytokines such as IL2, IL-18, and IFN, and other cytokines. IL-12 activates
the T-bet transcription factor, leading to IFN production

and acts synergistically with IL-18 to polarize the innate
immune response to a Th1, proinflammatory phenotype
[66]. IL-12 can be induced in monocytes by addition
of oxidized LDL, is expressed by lymphocytes, activated
macrophage and dendritic cells, and is detected in these cells
in atherosclerotic lesions. In animal models, atherosclerotic
lesions in ApoE/ mice are accelerated by injection of
recombinant IL-12 [97]. Concordantly, IL-12/ /ApoE/
double knockout mice have reduced atherosclerotic lesion
formation, and LDLR/ mice crossed with a mouse with
a mutation in which monocytes cannot secrete IL-12 also
have reduced plaque formation [98, 99]. Interestingly, IL12 is potently antiangiogenic and induces an antiangiogenic
program mediated by IFNg inducible genes [100]. It does
not appear that IL-12 has direct eects on resident vascular
cells; nevertheless, because of its induction of IFN, and its
potent Th1-polarizing eects, IL-12 is an attractive target for
antiatherosclerotic therapies.
3.3.7. IL-18. IL-18 is potently proinflammatory which may
be expected from a cytokine which is related to IL-1
and signals through a receptor with a high degree of
sequence homology to the IL-1 receptor. IL-18 and its
receptor are detected in human atherosclerotic plaque, and
importantly, IL-18 serum levels are elevated in patients with
coronary artery disease (CAD) [101]. IL-18 is produced
primarily by macrophage, but the IL-18 receptor is present
on macrophage, EC, and to a lesser degree, VSMC, which
suggests a role for this cytokine in bidirectional communication between inflammatory and vascular cells. IL-18 signal
transduction converges on NF-B and upregulates IL-6, IL-8,
and adhesion molecules on monocytes and EC, supporting
its proinflammatory and atherogenic properties [102]. IL18 has pro-atherosclerotic eects in several animal models.
Though not strictly in the Th1 category, IL-18 leans toward
being a Th1 interleukin because it induces production of
IFN [76]. Systemic administration of IL-18 significantly
increased atherosclerotic plaque in ApoE/ mice, and IL18/ApoE double knockout mice had smaller and more
stable lesions compared with control mice [103, 104]. IL18 has a synergistic relationship with IFN, as promotion of
atherosclerosis by exogenous addition of IL-18 is reduced in
IFN/ApoE double knockout mice [103, 104].
3.4. Antiatherogenic Cytokines. Cytokine abundance in atherosclerotic plaque is overwhelmingly Th1-oriented [35, 66].
Since so many more pro-atherogenic cytokines and receptors
have been identified and characterized, much greater eort
has gone into understanding these cytokines and potential
for inhibition of their expression or activity. Far fewer
studies have pursued characterization of anti-inflammatory
cytokines, but perhaps modulation of anti-inflammatory
or protective cytokines holds greater therapeutic potential.
This section will present both confirmed and potentially
antiatherosclerotic cytokines. IL-10, IL-33, and TGF have
been experimentally confirmed antiatherogenic cytokines.
9
3.4.1. IL-10. Interleukin-10 is the archetypal Th2 interleukin
and the most studied. IL-10 is a pleiotropic cytokine
produced by most immune cells, including macrophage,
monocytes, and T and B lymphocytes. IL-10 can be detected
in these cells in human atherosclerotic plaque. Expression
of IL-10 is associated with decreased apoptosis in the lipid
core of the lesion [105]. Multiple approaches demonstrate
that IL-10 is considered to be atheroprotective by multiple
mechanisms including, Th2 T-cell polarization; inhibition of
antigen presentation, inhibition of T-cell proliferation, and
attenuation of inflammatory gene expression in multiple cell
types [66, 106]. The molecular mechanisms of IL-10 activity
are complex. IL-10 signals through the IL-10 heterodimeric
receptor and activates the JAK/STAT pathway, principally
STAT3. IL-10 blocks TNF-induced MAPK signaling and
NF-B activation in monocytes, macrophage, EC, and VSMC
[37, 107]. In cultured monocytes, it has recently been shown
that IL-10 can reduce mRNA stability of inflammatory transcripts which contain A/U-rich regulatory elements (ARE)
regulatory elements in their 3 UTR [107]. In this way, IL-10
can dampen the inflammatory response in immune cells at
both the transcriptional and posttranscriptional levels.
EC and VSMC do not express IL-10, but IL-10 does have
multiple eects on vascular cells, suggesting unidirectional,
paracrine/juxtacrine signaling between resident vascular and
inflammatory cells. In cultured EC, IL-10 has no attenuating
eect on expression of inflammatory cytokines, but can
reduce ICAM-1 and VCAM-1 expression. In VSMC, IL10 did not reduce IL-1-induced expression inflammatory
cytokines, but did reduce VSMC proliferation in an NF-B
dependent manner [108].
Numerous mouse models utilized by various groups have
established IL-10 as potently antiatherogenic. In over expression studies, IL-10 transgenic mice have reduced atherosclerotic plaque burden, and transfer of bone marrow from IL-10
transgenic mice into LDLR/ mice reduced atherosclerosis
[109]. Systemic adenovirus-mediated IL-10 gene expression
reduced atherosclerosis by immune cell deactivation and
reduction in inflammatory cell infiltrate in plaque [110].
Interestingly, serum cholesterol is reduced in these mice,
which also may contribute to decreased vascular inflammation. IL-10 transgenic mice in the C57/B6 background fed
an atherogenic diet including cholate had reduced plaque
formation, and IL-10/ mice in the same background fed
the same diet had increased plaque compared with controls.
In each case, IL-10 levels correlated with leukocyte infiltration and production of inflammatory cytokines [109, 111].
Concordantly, atherosclerosis is increased in IL-10/ApoE
double knockout mice, and transfer of IL-10/ BM to
LDLR/ mice demonstrates that it is leukocyte-derived
IL-10 that mediates protective eects by polarizing the T
lymphocyte Th2/Th1 ratio toward a more anti-inflammatory
phenotype [111]. The synthesis of these studies demonstrates
that IL-10 is a potent immune modulator that can reduce
atherosclerosis by reduction in expression of inflammatory
genes, reduction in leukocyte/EC interactions, and polarization of adaptive immunity to the Th2 phenotype.
10
3.4.2. IL-33. IL-33 is an IL-1 family member expressed by
Th2 cells and is considered a Th2 interleukin because it
increases synthesis of IL-4, IL-5, and IL-13, while decreasing
IFN expression. IL-33 is expressed in normal artery, but is
increased in macrophage in human atherosclerotic plaque
[112]. IL-33 is expressed in several cell types, and expression
by macrophage expression has direct suppressive eects on
macrophage function. Mice injected with neutralizing decoy
receptor developed increased atherosclerotic plaque and had
reduced IL-5 expression and anti-oxLDL antibody [112]. In
ApoE/ mice fed a high-fat diet, IL-33 reduced macrophage
accumulation into atherosclerotic plaque, but plaque area in
these mice by en face staining was not directly assessed [112].
IL-33 can also diminish macrophage foam cell formation by
reducing lipid uptake and also increasing cholesterol eux in
these cells [113]. Proposed mechanisms for these eects are
reduced expression of scavenger receptors such as CD36 and
increased expression of genes, which promote cholesterol
eux such as ApoE, ABCA-1 [113].
3.4.3. TGF. Transforming growth factor is the prototypical and most studied member of a TGF superfamily which
currently includes at least 50 dierent proteins. TGF is
recognized by a complex family of receptors [114], which
signal through the SMAD family of signal transducers.
TGF is produced by macrophage, T lymphocytes, EC, and
VSMC, and detected in these cells in human atherosclerotic
lesions. TGF is decreased in serum of patients with severe
atherosclerosis (reviewed in [115]). TGF is considered to be
a beneficial cytokine for atherosclerosis, and its antiatherogenic protection is mediated by several mechanisms.
Initially recognized as a profibrotic, wound-healing
cytokine with VSMC as a major target, TGF has garnered
recent attention as a potent anti-inflammatory and Th2polarizing cytokine. TGF has immunomodulatory eects
on T-cell dierentiation within atherosclerotic lesions [116].
TGF plays an important role in T regulatory cell development as it is a costimulatory factor for FoxP3 expression,
and the ability of DC to promote T reg cell dierentiation
is dependent on TGF [117]. TGF knockout mice are
postnatally lethal, but interestingly, severe leukocyte infiltration was observed in every organ throughout the pup,
underscoring the potent immunomodulatory eects of this
cytokine [118]. Concordantly, TGF heterozygous mice fed
an atherogenic diet had increased atherosclerotic plaque,
endothelial activation, and leukocyte infiltrate [119].
TGF contributes to matrix deposition in lesions; administration of neutralizing antibody or soluble TGF receptor
to ApoE/ mice increases atherogenesis in those mice,
with lesions displaying decreased collagen content [120].
Further, when TGF is depleted by injection of mice with a
soluble TGF-receptor decoy, lesions with decreased collagen
content and concomitant intraplaque rupture were observed,
which is pertinent for human disease where plaque stability
is paramount [121]. Mice receiving bone marrow from mice
expressing a dominant-negative TGF receptor driven by a
T-cell-specific promoter demonstrated increased plaque, Tcell infiltration, and decreased VSMC and collagen content,

suggesting that T cells, rather than resident vascular cells,
are the major eector for TGF activity [121]. The synthesis
of these studies suggest that the pleiotropic activities of
TGF in matrix deposition, immune cell modulation, and
T reg development make it a promising subject of study
and an attractive therapeutic for attenuation of not only
atherosclerosis, but multiple vascular diseases.
3.4.4. IL-4. IL-4 is a confirmed Th2 interleukin produced by
activated T cells which promotes autocrine and paracrine
immunodampening eects on macrophage and T lymphocytes [37, 66], and some reviews consider IL-4 to be
atheroprotective [122]. IL-4 protein and mRNA are detected
in human atherosclerotic plaque. IL-4 signals through
STAT5, STAT6, and JAK proteins, and can suppress IL-1
and TNF synthesis in these cells. While conceptually this
should be an antiatherogenic cytokine, experimental data do
not fully support this assumption. For example, IL-4 can
induce VCAM-1 expression in EC which would presumably
expedite leukocyte extravasation and leukocyte retention
into the vessel wall. Yet other studies show that IL-4 can
inhibit macrophage adhesiveness and VSMC proliferation.
IL-4/ mice do not have increased atherosclerosis, and
subcutaneous injection of recombinant IL-4 into ApoE/
mice does not reduce development of atherosclerotic lesions
[123]. Further, lesions were actually reduced in area in
IL-4/ /ApoE/ double knockout mice, and reconstitution
of LDLR/ mice with IL-4/ bone marrow also reduces
lesion formation. IL-4 may represent an example where
a Th2 interleukin may not have a clearly direct role in
reduction of atherosclerosis, confirming the complexity of
the function of the interleukin as well as of atherosclerosis.
3.4.5. IL-19. IL-19 was identified and cloned by database
searching for IL-10 homologues [124, 125]. Consequently,
IL-19 was originally classified in an IL-10 subfamily which
includes IL-19, IL-22, and IL-24, but signals through dierent combinations of shared receptor chains complexes from
these other family members. IL-19 is considered to be Th2
interleukin because it is able to polarize the maturation of
human T cells away from the Th1 to the Th2 phenotypes
[126, 127]. IL-19 expression was originally assumed to
be leukocyte-specific; however, recent reports demonstrate
expression by inflammatory stimuli in EC and VSMC [124,
125, 128, 129]. Adenoviral gene delivery inhibits restenosis in
angioplasty injured rat carotid arteries [129]. IL-19 has yet to
be detected in human atherosclerotic plaque, but is expressed
in inflammatory and resident vascular cells in allografted
coronary arteries from human transplant patients [129],
suggesting that expression is likely in the inflammatory
milieu of the atherosclerotic lesion. Furthermore, recent
reports indicate that serum concentrations of IL-19 are
increased in patients undergoing coronary artery bypass
graft (CABG) surgery with cardiopulmonary bypass [130,
131]. In VSMC, IL-19 activates STAT3, decreases migration,
proliferation, and expression of inflammatory transcripts,
but in contrast to either IL-10 or IL-20, IL-19 does not inhibit
NF-B activity [132]. Rather, IL-19 decreases inflammatory

mRNA transcript stability by inhibition of the mRNA
stability factor HuR, which is known to recognize stability
elements on the 3 UTR of inflammatory transcripts [133].
Also in VSMC, IL-19 induces expression of the cytoprotective
and antiatherosclerotic protein heme oxygenase-1 [134].
Together, lymphocyte phenotype modulation, reduction in
inflammatory transcript stability, and induction of HO-1
represent multiple novel anti-inflammatory, and potentially
antiatherogenic mechanisms for IL-19.
4. What Therapies Hold the Most Promise?

What Should Be Points of Emphasis for
Future Research?
With the emphasis on lipid-initiated inflammation as the
driving factor for atherogenesis, it is perhaps not surprising
that several ecacious therapies are aimed at altering
the immune response. In this section, we present several
approaches for therapeutic potential which hold promising
possibilities for intervention.
4.1. Statins Are Anti-Inflammatory. Statins are atheroprotective by two mechanisms. Originally designed to target and
reduce elevated cholesterol, statins also confer cardiovascular
benefit by directly or indirectly modulating the inflammatory
component of atherosclerosis (reviewed in [135]). Statins
reduce endogenous cholesterol synthesis by inhibition of
HMG-CoA reductase, which is the rate-limiting enzyme
of the mevalonate pathway through which cells synthesize
cholesterol. However, interference with the mevalonate pathway also prevents the synthesis of isoprenoid intermediates
which play an important role in the posttranslational
modification of the small GTPases Rho, Rac, and Ras, which
act as molecular switches upstream of inflammatory signal
transduction pathways. Inhibition of isoprenylation results
inhibition of signal transduction pathways and downstream
gene transcription. Statins act on endothelial cells, smooth
muscle cells, macrophages, lymphocytes, and hepatocytes. In
this way, statins modulate inflammatory gene expression in
multiple cell types by diminishing activity of transcription
factors which regulate genes involved in a wide range of
atherogenic pathways. Inhibition of small GTPase activity
also modulates cytoskeletal dynamics, and subsequent cell
migration, membrane tracking, and membrane stability.
The beneficial anti-inflammatory side eects of statins
have reinforced the notion that lipid and inflammation
remain preeminent targets for antiatherosclerotic therapy,
but also point to the small GTPases and components of signal
transduction pathways as potential targets as well.
4.2. Inhibition of NF-B. Inhibition of inflammatory gene
expression is a potent antiatherosclerotic strategy. NF-B is
considered to be a master switch of inflammatory gene
expression [136]. NF-B is ubiquitous, and it is expressed
and active in all cells present in the atherosclerotic lesion.
More specifically, many cellular responses to oxidized lipids
and inflammatory stimuli are mediated by NF-B. One
approach to exploit NF-B as a target has been to regulate
11
its interaction with its endogenous regulatory proteins of
the IB family [137]. Several studies in diseases other
than atherosclerosis such as allograft vasculopathy and
angioplasty-induced restenosis have exploited this protein
as a target for vascular diseases, albeit with limited success.
One interesting approach has been the use of oligonucleotide decoy of NF-B consensus binding sites which
has been successful to limit restenosis following balloon
angioplasty [138]. Pharmacological inhibitors of NF-B have
been described in the literature and could be promising
antiatherosclerotic compounds. Clearly, with its position as
a central regulator of inflammatory and pro-atherogenic
gene expression, selective inhibition of this important transcription factor is a promising target of antiatherosclerotic
therapy.
4.3. Anticytokine Therapy. Activation of immune and resident vascular cells by atherogenic stimuli is initiated
and sustained by a complex network of cytokines. With
the preeminent role of cytokines in atherogenesis, they
hold obvious promise as targets to combat this disease. Approaches to blockade of bioavailability of proatherogenic cytokines include cytokine receptor antagonists, cytokine-specific monoclonal antibodies, and soluble
cytokine decoy receptors. Potent proinflammatory cytokines
including TNF, IL-1, and IL-18 have naturally occurring
endogenous inhibitors which could potentially be harnessed
as antiatherosclerotic therapy [139]. Use of a TNF receptor
protein has shown some ecacy to combat rheumatoid
arthritis, but eorts to attenuate atherosclerosis are forthcoming [140]. Considering pleiotropic and redundant roles
of many inflammatory cytokines, key issues of selectivity and
tissue specificity remain to be addressed.
4.4. Upregulation of Anti-Inflammatory Cytokines. If inhibition of proinflammatory cytokines hold promise for reduction of atherosclerosis, then induction of anti-inflammatory
cytokines also need to be considered as a viable therapeutic
approach. As discussed, several anti-inflammatory interleukins have potentially antiatherosclerotic eects, including
IL-4, IL-10, IL-19, and IL-33. Since overexpression has been
proposed to attenuate other inflammatory conditions such as
rheumatoid arthritis, colitis, and asthma, they may also prove
attractive as an approach for attenuation of atherosclerosis.
Several promising studies in atherosclerosis-susceptible mice
have implicated IL-10 as a potential antiatherosclerotic
therapeutic, but additional studies are necessary for IL-19
and IL-33 [106, 109111]. Caution needs to be taken as
increases in anti-inflammatory cytokines have the potential
for untoward side eects of immunosuppression and susceptibility to infection. One approach may be to administer
one or more anti-inflammatory cytokines to alter the balance
of Th1/Th2 cytokine ratio, thus modulating endogenous
adaptive immunity to a more anti-inflammatory profile.
Little has been published regarding potential protective
eects of Th2 interleukins on resident vascular cells in
addition to inflammatory cells. Presently, most studies which
focus on Th2 interleukins currently consider them to be
12
indirectly antiatherogenic by dampening the host immune
response, thus reducing inflammation and subsequent lesion
formation [37, 111]. However, recently, IL-19 has been
shown to reduce angioplasty-induced restenosis in rats, and
inflammatory gene expression in human VSMC [129, 132].
IL-19 has also been shown to induce HO-1 expression
and reduce ROS in human VSMC [134]. Together with its
Th2-inducing properties, IL-19 may represent an attractive
therapeutic modality to attenuate atherosclerosis.
4.5. Immunization. Immunization with oxidized LDL
induces antibody against oxLDL and significantly reduces
experimental atherosclerosis [141, 142]. Immunization with
other antigens, such as heat shock proteins or ApoB100
fragments, have also reduced athero in mice, implicating
vaccination as a promising approach to prevent or attenuate
atherosclerosis [143]. Importantly, immunization with
ApoB100 peptide induced antigen-specific T reg generation
[144]. The precise mode of action of protection remains to
be elucidated. It is speculated that induction of antibody
by immunization increases clearance of oxLDL; this is
supported by the observation that protection can be
correlated with the titer of the antibody [142]. Caution
needs to be taken to avoid molecular mimicry and crossreactivity that could have deleterious autoimmune responses;
nevertheless, future studies to determine the most eective
antigen and vaccination regimen need to be performed to
optimize this promising and novel strategy.
4.6. Stimulation of T Regulatory Cells. Considering the
antiatherogenic eect of T regulatory cells in attenuation of
atherosclerosis, therapy to induce generation of T reg cells is
potentially a powerful approach to attenuate atherosclerosis.
Several studies have pursued this approach. In one such
study, mice treated with CD3-specific antibody induced
CD4+ CD25+ T reg cells [145]. Further, these cells secrete
high levels of TGF, which dampens the immune response
as well as increases plaque stability. In theory at least,
any prolonged introduction of a peptide could stimulate T
regulatory cells and induce immunological tolerance. This
approach has been pursued as a therapy for allergies and
arthritis for several years, but has yet to be successfully
exploited to treat atherosclerosis.
5. Summary and Conclusions

Atherosclerotic vascular disease remains a significant cause
of mortality and socioeconomic burden in the westernized
world and will increase worldwide due to the adoption
of a western diet and sedentary lifestyle. Atherosclerosis is
an enormously complex and dynamic disorder involving
multiple cell types and soluble factors. Several types of
immune cells as well as resident vascular cells respond
to hyperlipidemic environment in a maladaptive fashion
resulting in localized vascular inflammation recognizes as
atherosclerotic plaque. However, we have learned much in
the previous two decades about the etiology, progression,
and maintenance of atherosclerosis. Our recent appreciation

that inflammation plays a critical role in atherosclerosis has
increased our opportunity to devise therapeutic treatment
to reduce or prevent atherosclerosis. As an example, since
the balance of pro- and anti-inflammatory cytokines dictates
plaque content and can determine plaque severity and stability, tipping the balance toward anti-inflammation may have
beneficial eects. Despite their complexity, modulation of
signaling pathways and transcription factors which regulate
expression of those cytokines also oer opportunity for
therapeutic intervention. However, many issues concerning
etiology, detection, cellular dynamics, and plaque vulnerability remain unresolved. In summary, vascular inflammatory
diseases in general and atherosclerosis in particular represent an opportunity and challenge. Our understanding of
atherosclerosis at the tissue, cellular, and molecular levels are
crucial in our ability to devise potent and specific therapeutic
modalities to combat this disease.
Acknowledgments
This work was funded by NHLBI HL090885. The author
would like to acknowledge original artwork by Matthew
Autieri.
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ISRN Vascular Medicine

1.1. Background. Atherosclerosis is recognized as a chronic,

ISRN Vascular Medicine

2. Cellular Components and

ISRN Vascular Medicine

Thin fibrous cap

Thick fibrous cap

Smooth muscle cell

ISRN Vascular Medicine

ISRN Vascular Medicine

ISRN Vascular Medicine

3. Cytokines, Cellular Communication,

ISRN Vascular Medicine

M, L, EC, and SMC

mitogenic, drive development, and influence fibrotic gene

3.3.1. IFN. IFN is expressed by most cell types present

ISRN Vascular Medicine

ISRN Vascular Medicine

ISRN Vascular Medicine

ISRN Vascular Medicine

4. What Therapies Hold the Most Promise?

5. Summary and Conclusions

ISRN Vascular Medicine

ISRN Vascular Medicine

ISRN Vascular Medicine

ISRN Vascular Medicine

antagonist and tumor necrosis factor binding protein on

ISRN Vascular Medicine

ISRN Vascular Medicine

Hindawi Publishing Corporation

Hindawi Publishing Corporation

Research and Treatment

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Submit your manuscripts at

Hindawi Publishing Corporation

Hindawi Publishing Corporation

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Oxidative Medicine and

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