Cardiovascular Research

Cardiovascular Research 2005 67(1):11-20; doi:10.1016/j.cardiores.2005.04.019

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Copyright © 2005, European Society of Cardiology

Interferon- and atherosclerosis: Pro- or anti-atherogenic?

Elizabeth J. Harvey and Dipak P. Ramji^*

Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, U.K.

^* Corresponding author. Tel./fax: +44 29 20876753. Email address: Ramji{at}cardiff.ac.uk

Received 10 February 2005; revised 1 April 2005; accepted 19 April 2005

	Abstract

Top Abstract 1. Introduction 2. Molecular biology of... 3. Role of IFN-{gamma}... 4. Anti-atherogenic roles of... 5. Lessons from mice 6. Concluding remarks References

 
Atherosclerosis is considered to be a form of chronic inflammation governed by a complex network of inter- and intra-cellular signaling pathways. The pleiotropic cytokine interferon- (IFN-) is a key pro-inflammatory mediator that is expressed at high levels in atherosclerotic lesions. IFN- regulates the function and properties of all the cell types in the vessel wall. The precise role of IFN- in atherogenesis is complex, with both pro- and anti-atherogenic actions being identified. This review will discuss these actions of the cytokine along with recent findings that have emerged from mouse models of atherosclerosis that are deficient in IFN- signaling.

KEYWORDS Atherosclerosis; Cytokines; Foam cell; Inflammation; Interferon-

	1. Introduction

Top Abstract 1. Introduction 2. Molecular biology of... 3. Role of IFN-{gamma}... 4. Anti-atherogenic roles of... 5. Lessons from mice 6. Concluding remarks References

 
Atherosclerosis, an underlying cause of heart attacks and stroke, is responsible for around half of all deaths in western societies, with increasing numbers in developing countries. It is a multifactorial disease in which genetic predisposition, age, stress, physical inactivity, dietary habits, diabetes, infection, smoking, hypercholesterolemia and hypertension are some of the main risk factors [1,2]. The pathology of the disease, which develops during the lifetime of an individual, can simplistically be broken down into three distinct phases: formation of fatty streaks; development of a complex lesion; and plaque rupture [1,2]. Atherosclerosis is initiated by damage to the endothelial lining of the arterial wall, increasingly believed to be mediated by oxidative stress [3], leading to changes in the permeability of endothelial cells, increased expression of adhesion molecules on their surface, and production of cytokines [1,2]. Monocytes and T-lymphocytes migrate from the circulation into the intima of the arterial wall [1,2]. The monocytes in the intima differentiate into macrophages, which then take up modified lipoproteins to transform into foam cells. Fatty streaks, often present in humans even from childhood, consist of an accumulation of such cholesterol-filled foam cells derived from macrophages [1,2]. The more advanced, complex lesion develops as smooth muscle cells (SMCs) from the arterial media migrate into the intima, where they may also take up lipoproteins to become foam cells [1,2]. A fibrous cap, consisting of SMCs and extracellular matrix (ECM) then forms, enclosing a necrotic core of lipid-rich debris that results from the death of accumulated foam cells by apoptosis or necrosis [1,2]. Other features of the complex plaque can include calcification and neovascularization [4]. It is the eventual rupture of the plaque that causes the clinical complications of atherosclerosis, including myocardial infarction and stroke. Vulnerable plaques usually have very thin fibrous caps and a higher number of inflammatory cells [1,2,4]. The maintenance of the fibrous cap is dictated by the production and the degradation of the matrix, both processes that are likely to be influenced by inflammation [2,4,5]. Calcification and neovasculization also influence the stability of the plaque [1,2,4,5]. Following plaque rupture, exposure to tissue factor in the core of the lesion initiates the coagulation cascade that leads to thrombosis [2,4,5].

The ‘response to injury’ hypothesis is a widely accepted model for atherogenesis. The disease is considered as an initially protective, inflammatory response to the accumulation of modified lipoproteins in the artery [1,2,4,5]. Although many risk factors are believed to influence the progression of atherosclerosis, hypercholesterolemia is undoubtedly the most important, being sufficient in itself to drive lesion formation [1,2,4,5]. Elevated levels of serum cholesterol lead to the deposition of low density lipoproteins (LDL) in the arterial wall. Oxidation of LDL by reactive oxygen species (ROS) and oxidative enzymes in the intima is thought to be the primary initiating event in atherosclerosis development [3,5]. Oxidized LDL (oxLDL) acts both as an inflammatory mediator itself, capable of stimulating the recruitment of immune cells, and by inducing an inflammatory response in the overlying endothelial cells (ECs) [2,3,5].

The expression of cytokines is very high in the region of the atheroma in comparison to normal arteries [6]. Levels of pro-inflammatory cytokines (e.g. IFN-, interleukin (IL)-6, -12, and -15, tumour necrosis factor- (TNF-)) have been demonstrated to be higher than those of anti-inflammatory mediators (e.g. IL-4, IL-10) [6]. Cytokines orchestrate the development of the atherosclerotic lesion throughout all stages of the disease [6]. Amongst the cytokines, IFN- is emerging as a key factor in the pathogenesis of atherosclerosis. This review will describe the properties and biological functions of IFN- along with our current understanding of its role in atherosclerosis.

	2. Molecular biology of IFN- and its biological functions

Top Abstract 1. Introduction 2. Molecular biology of... 3. Role of IFN-{gamma}... 4. Anti-atherogenic roles of... 5. Lessons from mice 6. Concluding remarks References

 
The IFN family of cytokines is divided into type I and type II IFNs [7]. Type I IFNs, including IFN-, -β, - and -, share notable sequence homology and are synthesized by most cell types [7]. On the other hand, IFN- is at present the only type II interferon identified and activates a distinct type II receptor [7]. The production of IFN- during inflammation is controlled by the release of cytokines such as IL-12 and -18 by antigen-presenting cells (primarily monocytes/macrophages and dendritic cells (DCs) [7]). IFN- itself is secreted mainly by natural killer (NK) cells and activated T-lymphocytes (CD4+ Th1 cells) but recent evidence indicates that it can also be produced by monocytes/macrophages, NKT cells, DCs and B cells when involved in the activation of cells in a local environment [7,8].

IFN- has a multitude of functions, displaying direct antiviral activity as well as a variety of immunomodulatory and inflammatory roles [8,9]. IFN- null mice develop with no obvious morphological defects but display an increased susceptibility to bacterial and viral infection [8,9]. Specific actions of IFN- signaling include: stimulation of antigen presentation through induced expression of Class I and II major histocompatibility complex (MHC) molecules on the surface of macrophages and T-lymphocytes; antigen processing; control of Th1 and Th2 balance; activation of macrophages, T-lymphocytes and NK cells; stimulation of cytokine production in target cells; and recruitment of cells to the site of injury through increased expression of chemokines and adhesion molecules [7–9]. IFN- also influences cellular state including regulation of the rate of proliferation, differentiation and apoptosis [8–10]. All of these properties potentially impact on the process of atherosclerosis development.

	3. Role of IFN- in atherosclerosis

Top Abstract 1. Introduction 2. Molecular biology of... 3. Role of IFN-{gamma}... 4. Anti-atherogenic roles of... 5. Lessons from mice 6. Concluding remarks References

 
Immunohistochemical studies have revealed localization of IFN- to the atherosclerotic lesion [6]. Plaque formation is most likely to occur at vascular branch points where blood flow is altered [5,11,12]. Th1 cells, believed to be largely proatherogenic, accumulate in these regions and the expression of IFN- is induced [1,2,5,6]. More recently, a key role for NKT cells, which exhibit the properties of both NK cells and T cells and secrete high levels of IFN-, has been identified in atherosclerosis [13,14]. Mice with low numbers of NKT cells display less atherosclerosis development than the wild type counterparts [13,14]. IFN- has a range of influences on disease progression, acting on all the major cell types of the plaque, and the overall effect is complex. A large number of genes are directly or indirectly regulated by IFN-, including approximately 25% of the macrophage transcriptome [15]. The expression of many such genes impacts on several areas of lesion development. While many of the changes in gene expression are pro-atherogenic, there are also a number of other, key genes for which the regulatory effects of IFN- are anti-atherogenic. The pro- and anti-atherogenic roles of IFN- are discussed below in detail, with Fig. 1 summarising the major actions of the cytokine along with key IFN- regulated genes implicated in the responses.

View larger version (32K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Role of IFN- in atherosclerosis. IFN-, produced predominantly by the infiltrating T lymphocytes and NKT cells, induces (+) or inhibits (–) the expression of the specific, or classes of genes shown, in endothelial cells, macrophages and smooth muscle cells. The action of these genes then causes the characteristic changes in the lesion such as recruitment of immune cells, plaque destabilization and foam cell formation. See text for more details. Abbreviations: ABCA1, ATP-binding cassette transporter A1; apoE, apolipoprotein E; ACAT, acyl-coenzyme A: cholesterol acyltransferase; ICAM-1, intercellular adhesion molecule-1; LPL, lipoprotein lipase; MCP-1, monocyte chemoattractant protein-1; MHC, major histocompatibility antigen; MMP, matrix metalloproteinase; NOS, nitric oxide synthase; SR-A, scavenger receptor A; VCAM-1, vascular cell adhesion molecule-1.

 
3.1. Pro-atherogenic role of IFN-
3.1.1. Recruitment of immune cells to the lesion
Growth of the atheroma occurs largely through continued recruitment of macrophages and T-lymphocytes, and also SMC migration and proliferation [1,2,5]. The lesions of apolipoprotein (apo) E or LDL receptor (LDLR)-null mice deficient in IFN- or its receptor have a dramatically reduced content of these cells, thereby indicating an important role for IFN- in this recruitment [16,17]. As detailed below, the action of IFN- in the recruitment of immune cells can be regulated in a number of ways.

3.1.1.1. Increased production of chemokines
The secretion of chemokines by lesional cells establishes a gradient by which immune cells in the blood stream are attracted to the site of the atheroma [1,2,4,5]. IFN- is responsible for the induced expression of a number of key chemokines and chemokine receptors [18,19]. Of particular importance to the development of atherosclerosis is the CC chemokine monocyte chemoattractant protein (MCP)-1, shown in several independent studies to be a pro-atherogenic factor and a potential therapeutic target for the disease [18,19]. MCP-1 is chemotactic for monocytes and T-cells, and its expression is induced dramatically by IFN- [20]. The chemokine has been detected in the lesion by immunohistochemistry and in situ hybridization, and elevated levels have been found in patients associated with risk factors for atherosclerosis [18,19]. Murine models of atherosclerosis that are also deficient in MCP-1 or its receptor gene show a marked reduction in cellularity and lesion area without any changes in the plasma lipid or lipoprotein levels [18,19]. In addition to its role in chemoattraction, MCP-1 causes adhesion of recruited cells to ECs and an increase in the polarization towards the Th1 type immune response (pro-inflammatory) over the Th2 response (anti-inflammatory), thereby further increasing IFN- production [18,19].

Other chemokines whose expression is also induced by IFN- in the lesion include macrophage inflammatory protein (MIP)-1 and β, IFN-inducible protein of 10 kDa (IP-10), monokine induced by IFN- (MIG), IFN-inducible T cell alpha chemoattractant (I-TAC) and CXC-chemokine ligand 16 (CXCL16) [18,19,21]. CXCL16 is a recently discovered chemokine that mediates the migration of activated Th1 cells, and is identical to the scavenger receptor SR-PSOX [21]. Apart from the recruitment of immune cells and SMCs via a chemokine gradient, chemokines also have roles in leukocyte extravasation and angiogenesis, a common feature of advanced plaques [18,19,22].

3.1.1.2. Cell adhesion molecules
The uptake of cells into the blood vessel intima at the site of plaque formation also requires cell adhesion molecules displayed on the luminal surface of the endothelium [1,2,4,5]. One of the earliest events in the development of the fatty streak is the induced expression of adhesion molecules including vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 [23]. IFN- is an important mediator of this response, inducing the expression of both VCAM-1 and ICAM-1 in ECs and SMCs [24,25]. Presentation of these proteins on the endothelium mediates the attachment of immune cells which then migrate into the subendothelial space where the lesion forms.

IFN- also increases the expression of integrins such as -5-β-1 integrin, on the surface of vascular SMCs [26]. This allows the cells to bind to the fibronectin component of the ECM providing a substrate for SMC migration to the lesion and, thereby, causing the cells to adopt a proliferative phenotype [26].

3.1.1.3. Cellular activation
The majority of macrophages and T-cells in the atherosclerotic lesion are in an activated state whereby they are primed to respond to activating stimuli such as bacterial antigens (or in the lesion, oxLDL) [1,2,5]. For both cell types, this involves the increased secretion of pro-inflammatory cytokines and chemokines so contributing to the inflammation and growth of the plaque [1,2,4,5]. IFN- is well known to stimulate both the differentiation of monocytes to macrophages and to cause the activation of both T-lymphocytes and macrophages [7–9].

3.2. Cholesterol accumulation in foam cells
The uptake of cholesterol as oxLDL by macrophages and SMCs, to form lipid-loaded foam cells, is a key process throughout all the stages of plaque development [1,2,5,27]. Foam cell formation is often viewed as a pathological imbalance in cholesterol homeostasis, which is maintained in healthy cells, and during the initial increase in the uptake of oxLDL under atherogenic conditions, through the balancing of cholesterol influx, via LDL- and scavenger-receptors, with cholesterol efflux pathways [1,2,5,27]. Cholesterol efflux occurs through two main pathways: passive diffusion with high density lipoprotein (HDL) as a cholesterol acceptor; and reverse cholesterol transport, which involves active efflux and is dependent on the apoA1 and apoE components of HDL [1,2,27]. Atheroma form when the cells fail to maintain an adequate cholesterol balance. IFN- regulates the expression of several genes that are key players in cholesterol metabolism (see below). Overall, incubation of macrophage-derived foam cells with IFN- decreases cholesterol efflux to HDL or apoE [28]. The cytokine causes a redistribution of intracellular cholesterol and an increase in cholesterol ester accumulation [28]. More recently, IFN- has been shown to impede reverse cholesterol transport and promote foam cell transformation in human THP-1 monocytes/macrophages [29].

3.2.1. Apolipoprotein E
ApoE is a protein component of lipoproteins and is responsible for the transport of cholesterol and other lipids between peripheral tissues and the liver [30]. In the vascular wall, apoE acts as a highly atheroprotective molecule [30]. ApoE-deficient mice are severely hypercholesterolemic and develop atherosclerosis even when fed with a low fat diet [30]. The mechanisms behind this extreme phenotype are complex but the atheroprotective effect of apoE is attributed largely to its role as a cholesterol acceptor during reverse cholesterol transport [30]. Secondary effects of apoE are to decrease the proliferation of ECs in the lesion, to prevent platelet aggregation, and to inhibit the migration and the proliferation of SMCs [30]. ApoE-deficient mice are commonly used as a model for the progression of atherosclerosis and to investigate the effects of the deletion of other genes linked to the disease [30]. IFN- has been demonstrated to decrease the expression of apoE in both monocytes and macrophages, and to increase its intracellular degradation [31]. Due to the pivotal role of apoE in atherosclerosis, this is likely to be an important factor in the overall atherogenic effect of the cytokine.

3.2.2. ATP-binding cassette transporter A1 (ABCA1)
One of the principal components of the reverse cholesterol transport system is ABCA1, which mediates transfer of cholesterol from the cell to apoE and apoAI components of HDL [32]. Mutations in the ABCA1 gene cause Tangier disease, an HDL-deficiency syndrome associated with the accumulation of cholesterol in tissue macrophages and prevalent atherosclerosis [32]. While complete knock-out of the ABCA1 gene in apoE null mice has no impact on atherosclerosis, mice transplanted with ABCA1-deficient bone marrow cells (so ensuring the production of macrophages lacking the transporter) display significantly more atherosclerosis than those given wild type bone marrow [32,33]. This is due to an effect of knock-out in other tissues on plasma lipoprotein homeostasis that appears to balance the macrophage specific effects [32,33]. Increased expression of ABCA1 in transgenic mice has also been found to protect against atherosclerosis [34]. The expression of ABCA1 is increased in macrophage foam cells but treatment with IFN- has been shown to inhibit this, independent of the general activation status of the cells [28]. In this way, IFN- could cause an imbalance in cholesterol homeostasis with the potential to promote foam cell formation.

3.2.3. Acyl coenzyme A: acylcholesterol transferase (ACAT)
The decrease of ABCA1 expression in macrophage foam cells by IFN- has also been associated with an increase in the expression of a second mediator of cholesterol metabolism, ACAT [28]. The majority of cholesterol in foam cells exists in the form of cholesterol esters. In the absence of a suitable acceptor (such as HDL), ACAT catalyses the intracellular formation of cholesterol esters from free intracellular cholesterol and long chain fatty acids [27]. Raised levels of ACAT1, the isoform principally found in macrophages, are associated with these cells in atherosclerotic plaques [27]. IFN- increases ACAT1 mRNA expression and enzymatic activity [28], and thereby may contribute to the accumulation of cholesterol esters and decrease cholesterol efflux by reducing the pool of free cholesterol available. Notably, the decrease in overall cholesterol efflux observed on addition of IFN- to the cells, is overcome by the ACAT inhibitor A58035 [GenBank] [28]. More recently, synergistic transcriptional activation of human ACAT1 gene by IFN- and all trans-retinoic acid has been seen in macrophages [35]. It should, however, be noted that the role of ACAT in atherogenesis is complex and deficiency of macrophage ACAT-1 has been shown to promote atherosclerosis in LDLR-deficient mice [36].

3.2.4. Cholesterol hydroxylase
Cholesterol efflux can also be reduced by IFN- through inhibited expression of cholesterol hydroxylase, a mitochondrial P450 enzyme, in ECs and monocytes/macrophages [37]. Hydroxylation of cholesterol to the oxygenated sterol, 27-hydroxyl cholesterol, by cholesterol hydroxylase protects against atherosclerosis development by promoting the removal of cholesterol from the cell and its transport to the liver for excretion [38,39]. Indeed, a functional deficiency of the enzyme in humans is associated with an increased risk of developing premature atherosclerosis [38,39]. In addition, the gene is expressed at high levels in atherosclerotic lesions, where it co-localizes with macrophages [39].

3.3. Complex plaque formation and thrombosis
As the disease progresses, the atherosclerotic lesion becomes increasingly complex and the advanced plaque may include features such as calcification and neovascularization [2,4]. As discussed previously, neovascularization and angiogenesis may be increased by IFN- via induced expression of certain chemokines. IFN- may also have a role in the mechanisms of calcification through an increase in the expression of 1--hydroxylase [40,41]. This enzyme is responsible for catalysing the conversion of 25-hydroxyvitamin D to 1-, 25-dihydroxyvitamin D, an active metabolite of vitamin D that contributes to calcification [41]. IFN- also affects foam cell apoptosis and plaque destabilization, and these aspects are discussed below in detail.

3.3.1. Foam cell apoptosis
Production of ECM components by SMCs contributes to the formation of a fibrous cap on the luminal side of the lesion [1,2]. Beneath this cap, the advanced plaque contains a lipid filled necrotic core, formed as foam cells in the lesion die and release their contents [1,2]. Cell death in the atherosclerotic lesion occurs primarily through the process of apoptosis [1,2]. The function of IFN- in apoptosis is complex and the cytokine can have either a pro- or anti-apoptotic effect depending on the specific state of the cell [9]. Inagaki et al. [42] have shown that IFN- can stimulate apoptosis of macrophage foam cells. IFN-stimulated genes with apoptotic functions in macrophages include TRAIL, Fas, and caspases 4 and 8 [42,43]. Induced expression of caspases by IFN- in monocytes and macrophages has been shown to enhance susceptibility to apoptosis [44]. The apoptosis of vascular SMCs has similarly been shown to be promoted by IFN- [45].

3.3.2. Plaque destabilization
Blockage of the artery by the atherosclerotic plaque itself is rarely sufficient to cause the clinical complications such as acute unstable angina, myocardial infarction or stroke [1,2,5]. The atheroma may be present for decades with few symptoms and it is only the eventual rupture of the plaque that leads to thrombosis and embolism [1,2,5]. Rupture of the fibrous cap exposes tissue factors present in the necrotic core so that the coagulation cascade is initiated leading to thrombosis formation [1,2,5]. Certain factors contribute to the likelihood of plaque rupture by affecting the composition and stability of the fibrous cap. For example, particular arterial sites, such as branches or curvatures where blood flow is altered, are predisposed both to lesion formation and the generation of thin fibrous caps prone to rupture [11]. The expression of pro-inflammatory cytokines by ECs has been shown to be increased in such regions [11,12]. Such induced expression is believed to occur through shear stress regulatory elements (SSREs) present in the control regions of target genes [11]. The cocktail of cytokines in and around the atheroma contributes to plaque stability through the regulation of various genes [11,46]. IFN- producing Th1 cells frequently accumulate at the sites of plaque rupture and there are several mechanisms by which the cytokine can contribute to destabilization of the plaque [11,46].

The fibrous cap is composed principally of ECM components synthesized by SMCs, including elastic filament and proteoglycans with collagens providing most of the tensile strength [1,2]. Lesions with a high foam cell content and low ECM have been shown to be more likely to rupture and cause thrombosis formation [1,2,5]. Increased cellularity of the lesion caused by exposure to IFN- has already been discussed but the cytokine can also act to weaken the protective cap [16,17]. The expression of a number of collagen genes (e.g. collagens 1 and 3), as well as SMC proliferation and matrix synthesis, is inhibited by IFN- [47,48].

Matrix metalloproteinases (e.g. MMP-1, 2, 3 and 9) have been found to be present in the lesion, particularly localized to shoulder regions where plaque rupture is more likely [49]. These enzymes break down the ECM and thus cause plaque destabilization. IFN- is known to stimulate increased production of these MMPs by macrophages and SMCs [50]. Tissue factor activity is also enhanced by IFN- treatment in synergy with C-reactive protein, so increasing the rate of thrombosis following rupture [51].

	4. Anti-atherogenic roles of IFN-

Top Abstract 1. Introduction 2. Molecular biology of... 3. Role of IFN-{gamma}... 4. Anti-atherogenic roles of... 5. Lessons from mice 6. Concluding remarks References

 
Despite the range of pro-atherogenic functions of IFN- discussed so far, certain modulations in gene expression caused by this cytokine appear to be atheroprotective. Treatment of monocyte/macrophage cells with IFN-, in vitro, has been demonstrated, in some cases, to reduce both the oxidation of LDL and the uptake of oxLDL [52,53]. A recent study has also found that transplantation of IFN--deficient bone marrow in LDLR–/– mice increases the extent of atherosclerosis development [54], suggesting that IFN- secreted by bone marrow-derived cells (T-lymphocytes and monocytes/macrophages) has an atheroprotective effect. Notably however, the lesions in these mice were composed mostly of macrophage-derived foam cells and had a high collagen content suggesting that they were less susceptible to rupture [54]. The seemingly contradictory pro- and anti-atherogenic roles of IFN- can be compared to the cytokine's similarly conflicting pro- and anti-inflammatory effects. While IFN- is primarily considered to be a pro-inflammatory cytokine [7], it induces the expression of a number of anti-inflammatory proteins, such as IL-8, IL-1 receptor antagonist and IL-18 binding protein, in a range of cell types [55].

4.1. Reduced uptake of oxLDL
4.1.1. Scavenger receptors
Under normal physiological conditions, scavenger receptors (SRs) serve to clear up cellular debris and bind bacterial pathogens in host defence. In atherosclerosis, SRs, most significantly SR-A and CD36, are the principle mediators of oxLDL uptake in foam cell formation [27,56]. Lipid loading takes place initially through binding of modified lipoproteins to surface receptors, such as LDL-R, in addition to the SRs [1,2,27]. However, LDL-R expression is down-regulated through the sterol regulatory element-binding protein pathway as cholesterol accumulates, while SRs, which are not subject to such feedback regulation, continue to take up increasing amounts of lipoprotein [57]. ApoE null mice that are also deficient in CD36 and SR-A show a significantly decrease in atherosclerotic lesion size and, additionally, the macrophages from these animals display a reduction in the uptake of acetyl-LDL in vitro [56].

IFN- has been shown to inhibit the expression of SR-A and CD36 specifically in macrophages, and it is primarily to this effect that reductions in macrophage foam cell formation by the cytokine are attributed [58]. It is interesting that IFN- also decreases the expression of very low density lipoprotein receptor and LDL-receptor related protein, which have also been implicated in atherosclerosis because they have a high binding affinity for atherogenic remnant particles [59,60].

4.1.2. Lipoprotein lipase
The physiological role of lipoprotein lipase (LPL) in lipid metabolism is to catalyze the hydrolysis of the triacylglycerol component of VLDL and chylomicrons to provide non-esterified fatty acids and 2-monoacylglycerol for tissue utilization [61]. LPL plays a complex role in atherogenesis with both pro- and anti-atherogenic actions being reported [61,62]. The enzyme expressed by the adipose tissue and muscle is considered to be anti-atherogenic because it aids in the clearance of circulating lipoproteins [61,62]. On the other hand, LPL expressed by macrophages is pro-atherogenic [61,62]. The main evidence for a pro-atherogenic action of macrophage LPL comes from a series of bone marrow transplantation studies (reviewed in Ref. [62]). For example, mice transplanted with LPL null bone marrow (therefore producing LPL-deficient macrophages) exhibit decreased atherosclerotic development [62]. It is believed that the lipolysis of VLDL and chylomicrons by LPL increases the formation and uptake of atherogenic lipoprotein remnants. Additionally, the enzyme on the surface of macrophages acts as a molecular bridge, causing the accumulation and, thereby, uptake of oxLDL to form foam cells [61,62]. We have shown previously that IFN- reduces LPL gene expression in macrophages at the transcriptional level, and this represents an atheroprotective effect [63].

4.2. Effects on oxidative stress in the vascular wall
In certain studies, IFN- has been found to inhibit macrophage-mediated LDL oxidation, a crucial step in the development of atherosclerosis [52,53,64,65]. IFN- has various effects that may contribute to changes in oxidative stress in the vascular wall and thus affect the oxidation of LDL. Of particular importance is the regulation of nitric oxide (NO) production. Signaling by IFN-, in particular in synergy with lipopolysaccharide (LPS) or other cytokines (e.g. TNF-, IL-2, transforming growth factor-β (TGF-β), IL-4), leads to an up-regulation of inducible nitric oxide synthase (iNOS) gene expression in a wide variety of cell types, including ECs, SMCs and macrophages [66]. The subsequent increase in NO plays a role in mediating many of the antiviral and antimicrobial effects of IFN-, participating directly in the killing of parasitic cells [67].

Increased generation of NO, which acts as a potent anti-oxidant, in response to IFN- may be responsible for the observations that the cytokine counteracts the oxidation of LDL [64]. Indeed, iNOS-deficient mouse macrophages disclose a pro-oxidant effect of IFN- on LDL oxidation [68]. NO also has a number of other anti-atherogenic effects, including: inhibition of immune cell recruitment to the lesion by counteracting the increase in VCAM-1 expression on ECs; blocking nuclear factor-kappa B (NF-B) signaling which is important for many pro-inflammatory pathways; and decreasing the proliferation of VSMCs and both T-cell activation and proliferation, leading to reduced cytokine production (including IFN-) [67–70]. Knock-out of endothelial nitric oxide synthase (eNOS) in mice has been shown to increase atherosclerotic lesion formation [71]. It should, however, be noted that at high vascular concentrations of NO, a reaction is promoted with superoxide to form peroxynitrite, an oxidant stronger than superoxide itself [69]. In fact, where eNOS is overexpressed it has been shown to accelerate atherosclerotic lesion formation in apoE-deficient mice [72–74]. It has also been suggested that graft arteriosclerosis is promoted by IFN- through dysregulation of eNOS and iNOS in graft infiltrating leukocytes [75].

IFN- also regulates the expression of a number of other genes implicated in the control of oxidative stress and oxidation of LDL. A consensus on the action of such gene regulation has, however, not emerged as some effects are atheroprotective whereas the others are pro-atherogenic. For example, IFN- induces the expression of extracellular-superoxide dismutase, which protects cells from oxidative stress via removal of reactive oxygen species (ROS) [76]. In addition, the expression of myeloperoxidase, implicated in the development of atherosclerosis through the production of ROS, is suppressed by IFN- [77,78]. Furthermore, IFN- decreases the expression of 15-lipooxygenase, which has been linked to the oxidation of LDL [53,79]. On the other hand, the cytokine has been demonstrated to stimulate the secretion of ROS by macrophages, ECs and neutrophils [80–82]. This may be because of the induced expression of vascular enzymes such as NADPH oxidase [83] and xanthine oxidase [84].

	5. Lessons from mice

Top Abstract 1. Introduction 2. Molecular biology of... 3. Role of IFN-{gamma}... 4. Anti-atherogenic roles of... 5. Lessons from mice 6. Concluding remarks References

 
Table 1 summarizes the findings from studies into the effect of IFN- on atherosclerotic lesion formation in mice. Compound-deficient mice in apoE and IFN- or IFN--R exhibit significant reductions in diet-induced atherosclerosis compared with apoE–/– mice [16,85]. Recently, compound-deficient mice in LDL-R and IFN- have also been shown to exhibit decreased atherosclerosis compared to LDL-R–/– mice [17]. Furthermore, administration of exogenous IFN- enhances atherosclerosis in apoE-deficient mice and IL-18 has also been shown to increase atherosclerosis in apoE-deficient mice through the release of IFN- [86,87]. Interestingly, IFN- has been found to elicit arteriosclerosis in the absence of leukocytes mediated through actions on vascular SMSs [88]. As mentioned previously, Th1 and NKT cells, both of which secrete large amounts of IFN- and localize to sites of lesion formation, have been shown to be pro-atherogenic in mouse models of the disease [6,13,14]. Inhibition of Th1 polarization leading to decreased IFN- secretion is also atheroprotective [89]. In a directly clinically relevant situation, there is a reduced incidence and severity of transplant arteriosclerosis following heart grafts in IFN--deficient mice [90,91]. In contrast to these findings, a recent study by Niwa et al. [54] showed that IFN- produced by bone marrow-derived cells delayed the progression of atherosclerosis. The results in relation to changes in lipoprotein levels have also been controversial. For example, exogenous administration of IFN- in apoE-deficient mice decreases serum cholesterol levels but enhances atherosclerosis [86]. In another study, however, IFN-- deficiency in male apoE-deficient mice was associated with no changes in plasma lipoproteins but reduced atherosclerosis [85].

View this table: [in this window] [in a new window]   Table 1 Effects of IFN- on atherosclerotic lesion formation in mice

 

	6. Concluding remarks

Top Abstract 1. Introduction 2. Molecular biology of... 3. Role of IFN-{gamma}... 4. Anti-atherogenic roles of... 5. Lessons from mice 6. Concluding remarks References

 
The role of IFN- in the pathology of atherosclerosis is undeniably complex and the pro-atherogenic versus anti-atherogenic nature of the cytokine has long been a subject for debate. While it is still not currently possible to reconcile all the conflicting evidence, the majority of research from mouse models of the disease that are deficient in IFN- signaling points towards a largely pro-atherogenic role. However, such a plethora of genes are regulated by IFN- that it is hard to determine the impact of each of these on the disease. Substantial evidence exists that some of these gene regulatory events are anti-atherogenic. It is possible that the role of IFN- may depend on the stage of the pathology and the presence of other factors in the atheroma, and mice that are deficient in IFN- signaling represent an extreme situation. Further research is, therefore, clearly needed into the phenotypic effects of this cytokine on various areas of complex plaque growth (e.g. foam cell formation, angiogenesis, calcification, plaque rupture) and into the specific signaling pathways involved in the regulation of individual genes, with the hope of identifying potential therapeutic targets in order to combat this disease.

	Acknowledgements

 
We thank the British Heart Foundation for financial support.

	Notes

 
Time for primary review 20 days

	References

Top Abstract 1. Introduction 2. Molecular biology of... 3. Role of IFN-{gamma}... 4. Anti-atherogenic roles of... 5. Lessons from mice 6. Concluding remarks References

 

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