Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Exp Med. Aug 20, 2015; 5(3): 154-159
Published online Aug 20, 2015. doi: 10.5493/wjem.v5.i3.154
Interferon-γ: Promising therapeutic target in atherosclerosis
Joe WE Moss, Dipak P Ramji
Joe WE Moss, Dipak P Ramji, Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, United Kingdom
Author contributions: Both authors contributed to this manuscript.
Conflict-of-interest statement: The authors do not have any conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Dipak P Ramji, Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, United Kingdom. ramji@Cardiff.ac.uk
Telephone: +44-29-20876753 Fax: +44-29-20874116
Received: March 17, 2015
Peer-review started: March 18, 2015
First decision: April 10, 2015
Revised: April 21, 2015
Accepted: May 7, 2015
Article in press: May 8, 2015
Published online: August 20, 2015


Atherosclerosis is a chronic inflammatory disorder of the vasculature and is the primary cause of cardiovascular disease (CVD). CVD is currently the world’s leading cause of death and the numbers are predicted to rise further because of a global increase in risk factors such as diabetes and obesity. Current therapies such as statins have had a major impact in reducing mortality from CVD. However, there is a marked residual CVD risk in patients on statin therapy. It is therefore important to understand the molecular basis of this disease in detail and to develop alternative novel therapeutics. Interferon-γ (IFN-γ) is a pro-inflammatory cytokine that is often regarded as a master regulator of atherosclerosis development. IFN-γ is able to influence several key steps during atherosclerosis development, including pro-inflammatory gene expression, the recruitment of monocytes from the blood to the activated arterial endothelium and plaque stability. This central role of IFN-γ makes it a promising therapeutic target. The purpose of this editorial is to describe the key role IFN-γ plays during atherosclerosis development, as well as discuss potential strategies to target it therapeutically.

Key Words: Atherosclerosis, Interferon-γ, Inflammation, Neutralization, MicroRNA

Core tip: Atherosclerosis is an inflammatory disorder of the vasculature and studies in mouse model systems have highlighted the beneficial effects of counteracting inflammation in limiting the progression of this disease. Due to its key role in inflammation and atherosclerosis development, interferon-γ (IFN-γ) is seen as a promising therapeutic target. In this editorial we discuss the role of IFN-γ in atherosclerosis together with potential therapeutic approaches against this cytokine and its key downstream targets.


Atherosclerosis is the underlying cause of cardiovascular disease (CVD) such as myocardial infarction (MI) and stroke. The World Health Organisation estimated that there were 17.5 million deaths from a CVD-related event in 2012, equating to approximately 1 in 3 global deaths[1]. The number of global deaths related to CVD has been predicted to increase due to rises in the incidences of obesity and diabetes and the acquisition of a westernised diet in developing countries. The disease is a major healthcare and economic burden and therefore there is a need to understand the disease in more detail and to develop new therapeutic approaches.


Atherosclerosis is a chronic, inflammatory disease characterized by the formation of foam cells in initial atherosclerotic lesions which then progress into advanced plaques. Low-density lipoprotein (LDL) can become trapped in the intima of medium and large arteries and modified to oxidized LDL (OxLDL). The presence of OxLDL triggers an inflammatory response in the neighbouring endothelial cells (ECs), causing the release of a variety of pro-inflammatory cytokines and chemokines, and expression of adhesion molecules on the cell surface (activation of ECs). These factors include macrophage chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) as well as P- and E-selectins[2,3]. Such pro-inflammatory molecules guide circulating monocytes in the blood stream to the OxLDL accumulation in the intima of arterial walls and aid the progression of atherosclerosis development[4-6]. Once in the intima the monocytes become exposed to macrophage colony-stimulating factor, triggering their differentiation into macrophages as well as inducing scavenger receptor (SR) expression on their surface[2,7]. Macrophages are then able to uptake OxLDL by SR-mediated endocytosis, macropinocytosis or phagocytosis and develop into foam cells, causing the appearance of the initial lesions and fatty streaks in arteries, which can then progress into mature plaques[8,9].

Mature atherosclerotic plaques are made up of vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM), as well as accumulated OxLDL, cholesterol and apoptotic cells, which form a lipid-rich necrotic core[10]. During plaque progression VSMCs proliferate and migrate towards the LDL accumulation and form a fibrous cap, which is tightly controlled and influenced by the nearby macrophages, ECs and T-cells[2,11]. As the fibrous cap continues to develop it forms a stable lesion by covering the large lipid-rich necrotic core, therefore the balance of ECM production and degradation can affect the stability of the lesion[2]. If the plaque ruptures it triggers a thrombotic reaction and in turn platelet aggregation, which can quickly impede or obstruct blood flow through the artery[7]. Depending on the location of the rupture it can potentially cause a MI or stroke. Therefore acute CVD events may be manageable by affecting plaque stability and preventing them from rupturing[7,12]. Amongst the cytokines involved in the development of atherosclerosis, interferon-γ (IFN-γ) is potentially a master regulator and will therefore be addressed in more detail.


IFN-γ is a key pro-inflammatory cytokine in atherosclerosis development as it is capable of inducing the expression of approximately a quarter of genes expressed in macrophages[3]. Immune cells present in the atherosclerotic lesions, including T-lymphocytes, natural killer T-cells, macrophages and other antigen presenting cells, secrete IFN-γ at pronounced levels[13,14]. Stimulation of many signaling pathways that regulate the immune and inflammatory responses can be induced by IFN-γ. The major signaling pathway that IFN-γ signals through is the Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) pathway[3].

JAK-STAT pathway

The IFN-γ cell surface receptor complex (IFN-γR) is made up of two subunit pairs (IFN-γR1:IFN-γR) which dimerize upon binding of the cytokine[13]. Bound to each subunit are two JAKs 1 and 2, which become activated by phosphorylation of tyrosine residues in the N-terminus in a mainly JAK2-dependent process[15]. Once activated, the JAKs phosphorylate the tails of the IFN-γR which triggers the recruitment of STAT1 monomers from the cytoplasm that then interact with the receptor via their src-homology 2 domains[16]. The recruited STAT1 monomers are then phosphorylated by the JAKs at tyrosine 701 and dissociate from the receptor complex to form STAT1:STAT1 homodimers[3]. The dimer is then able to translocate into the nucleus and stimulate the transcription of IFN-γ target genes, such as MCP-1 and ICAM-1, by binding to γ-activated sequence (GAS) elements in their promoters[13,15]. Furthermore, extracellular signal-regulated kinase (ERK) and other kinases are capable of phosphorylating the homodimer at serine 727 for maximal activity[17].


Therapeutically targeting IFN-γ in order to reduce the incidence of CVD represents a promising avenue due to its pro-inflammatory functions during atherosclerotic plaque formation, including the recruitment of immune cells to the site of OxLDL accumulation, foam cell formation, and plaque development and stability. A 2-fold increase in the size of atherosclerotic lesions has been reported in the Apolipoprotein E (ApoE) deficient mouse model that was injected with recombinant IFN-γ every day, even with a 15% reduction in plasma cholesterol levels[18]. Furthermore, ApoE deficient mice which also lacked IFN-γR showed a reduction in atherosclerosis development, as well as a 60% decrease in lipid build up in the lesions when fed on a western diet[19]. Deficiency of STAT1 in mouse model systems is also associated with reduced atherosclerosis development and foam cell formation, highlighting the key role of the JAK-STAT1 pathway in IFN-γ signaling during plaque progression[20,21].

Recruitment of immune cells

IFN-γ is a key recruiter of immune cells in the development of atherosclerosis and therefore important in the growth of lesions[22]. IFN-γ has been shown to be localized in atherosclerotic lesions and mice models lacking either IFN-γ or its receptor have been reported to have a reduced cellular content in their lesions[19,23,24]. The expression of key pro-atherogenic chemokines and their receptors, such as MCP-1 that has been detected in atherosclerotic lesions by immunohistochemistry and in situ hybridization, can be induced by IFN-γ[25,26]. Mouse models which were deficient for either MCP-1 or its receptor showed a reduced cellular content in lesions, as well as a reduction in the size of the lesions without changes in circulating lipid or lipoprotein levels[25]. IFN-γ can also influence the recruitment of immune cells by inducing the expression of adhesion molecules, such as ICAM-1 and VCAM-1, in ECs during the early stages of atherosclerosis development[27,28].

Foam cell formation

Cholesterol uptake and efflux is carefully balanced during homeostasis of this sterol in healthy cells. The formation of foam cells can be regarded as a pathological imbalance in favour of reduced cholesterol efflux and increased uptake of OxLDL[7,29]. The expression levels of a number of key genes involved in cholesterol metabolism are regulated by IFN-γ, including ApoE, ATP-binding cassette transporter A1 (ABCA1) and acetyl-CoA acetyltransferase 1 (ACAT1)[22]. In vitro studies that have incubated macrophage-derived foam cells with IFN-γ have shown a reduction in cholesterol efflux via increasing the expression of ACAT1 and attenuating the expression of ABCA1, resulting in increased accumulation of intracellular cholesteryl esters which promote the formation of foam cells[30]. Furthermore, the expression of several key SRs in foam cell development, including SR-A and SR that binds phosphatidylserine and oxidized lipids (SR-SPOX; also known as CXCL16), have been shown to be increased in human THP-1 and primary macrophages stimulated with IFN-γ, resulting in an increased uptake of OxLDL[31-33]. Therefore IFN-γ is capable of altering cholesterol homeostasis towards lower cholesterol efflux and higher retention of OxLDL in macrophages and contributes to foam cell formation.

Plaque progression and stability

IFN-γ can influence a variety of processes involved in the development of the early atherosclerotic lesions into mature plaques as well as their stability. Part of plaque development involves the migration of VSMCs and the formation of the fibrous cap. IFN-γ induces the expression of integrins on the surface of VSMCs which are capable of binding to fibronectin in ECM, triggering the VSMCs to differentiate from their inactive to their proliferative phenotype allowing migration towards the lesion to form the fibrous cap[34]. The stability of atherosclerotic plaques relies on the balance of ECM production and degradation which can also be affected by IFN-γ[2,22]. Foam cell apoptosis is also promoted by IFN-γ and causes them to expel their contents into the intima, contributing to the lipid-rich necrotic core and ECM degradation[35,36]. The balance can be tipped further towards ECM degradation by IFN-γ-mediated inhibition of the expression of several collagen genes, thereby suppressing matrix synthesis by VSMCs and resulting in reduced plaque stability and increased risk of a rupture[7]. ECM degradation can also be triggered by matrix metalloproteinases (MMPs) which are found in atherosclerotic plaques and are often localized to the shoulder regions where a rupture is more likely to occur[37]. MMPs are released by macrophages and VSMCs and their expression can be induced by IFN-γ stimulation[38].


Due to the high prevalence of CVD there are a variety of therapeutics designed to reduce various aspects of atherosclerosis development, including decreasing serum cholesterol levels and altering the expression of genes that are involved in cholesterol metabolism or the inflammatory response[3,39]. Statins, the most widely used and successful cholesterol lowering therapy class of drugs, are primarily designed to inhibit the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMG CoA reductase)[3]. HMG CoA reductase catalyses the rate limiting step in cholesterol biosynthesis, thereby lowering the levels of circulating LDL[40]. However there is a marked residual risk of CVD in patients on statin therapy, with a significant proportion unable to attain their target LDL levels even when receiving the highest recommended dosage, stressing the importance of developing new therapeutics[2,41].

One new potential therapeutic target is IFN-γ due to its key roles in atherosclerosis development. There are currently two strategies that have been developed that either target IFN-γ directly (IFN-γ neutralization) or inhibit its signaling pathways. Statins and agonists of nuclear receptors also attenuate IFN-γ actions in part by modulating its signal transduction pathways[42-44]. In human macrophages, IFN-γ-induced phosphorylation of STAT1 on serine 727 can be blocked using adenosine[45]. Work by Lee et al[46] has shown that stimulation of the adenosine A3 receptor with a novel agonist, thio-CL-IB-MECA, resulted in attenuated IFN-γ-induced STAT1-dependent gene expression. Furthermore a naturally occurring phenol in plant extract, resveratrol, is capable of preventing STAT1 phosphorylation at tyrosine 701 or serine 727 as well as JAK2 activation in human macrophages in vitro[47]. These compounds represent promising avenues for therapies targeted at the downstream signaling events in the JAK-STAT pathway in order to reduce the pro-inflammatory effects of IFN-γ. Other therapies target IFN-γvia alternative signaling pathways, for example, ACS14 (a hydrogen sulphide releasing aspirin) is capable of attenuating the expression of IFN-γ-stimulated CX3 chemokine receptor 1 (CX3CR1) via a peroxisome proliferator-activated receptor-γ-dependent mechanism[48]. Hydrogen sulphide has previously been shown to exert anti-atherogenic effects and its use in ACS14 has been shown to reduce atherosclerosis development in ApoE mice models[48,49].

IFN-γ neutralization involves the use of a soluble IFN-γR (sIFN-γR) which acts as decoy receptor to prevent the activation of IFN-γR and in turn the phosphorylation of STAT1 in the JAK-STAT pathway, in effect “neutralizing” the IFN-γ. The approach was first developed by Koga et al[50], and demonstrated in ApoE mice which were fed a high fat diet for 8 wk and given two intramuscular injections of a plasmid encoding sIFN-γR at weeks 4 and 6. Compared to the control mice, those that received the sIFN-γR injections had dramatically reduced atherosclerotic lesion size as well as greater plaque stability. This increase in plaque stability was found to be due to an increase in the number of VSMCs in the fibrous cap in addition to greater collagen deposition. Additionally, there was also a decrease in the amount of lipid accumulation and number of macrophages in the necrotic core, which further improved plaque stability and reduced the risk of rupture. Furthermore, neutralizing antibodies have been used for other cytokines such as IL-1β and show great therapeutic promise[51,52], therefore similar strategies could potentially be developed to use antibodies to achieve IFN-γ neutralization.

Although targeting IFN-γ in atherosclerosis development may result in reduced lesion size and improved plaque stability, there are potential drawbacks that need to be assessed before IFN-γ targeting can be recommended therapeutically. The major concern involves the systemic inhibition of IFN-γ due to the major role it performs in the immune response[53]. Sustained universal inhibition of IFN-γ may increase an individual’s risk of acquiring intracellular infections and tumour development[53]. On the other hand it may benefit those high-risk patients who are unable to achieve target LDL plasma levels using currently available therapeutics. A possible solution to overcome universal inhibition would be to try and develop a drug delivery system, for example using nanoparticles, that would allow IFN-γ-targeted therapeutics to be delivered to a specific location rather than system wide[53,54].

Another possible solution would be to target further downstream targets of the IFN-γ signaling pathways, either alone or in combination with therapies that target IFN-γ directly. IFN-γ is known to induce the expression of several microRNAs (miRNAs) in addition to having its own expression regulated by miRNAs[55]. miRNAs are short non-coding single-stranded RNAs approximately 19-25 nucleotides in length that are evolutionary conserved in eukaryotic organisms[56]. Evidence is continuously accumulating that indicates that miRNAs are capable of regulating gene expression by inhibiting translation or inducing targeted mRNA degradation[57]. miRNAs have also been found to regulate a number of key steps during atherosclerosis development, including the inflammatory response triggered by IFN-γ[58-60]. One miRNA that is thought to play a key role in atherosclerosis development is miR-155. Evidence for the role of miR-155 in the inflammatory response was found by O’Connell et al[61]. miR-155 was the only miRNA out of 200 tested that was considerably up-regulated in primary murine macrophages after being treated with pro-inflammatory stimulants. Additional evidence for the involvement of miR-155 in the inflammatory response comes from studies which have shown its levels to be up-regulated in macrophages in atherosclerotic lesions as well as having an association with increased pro-inflammatory cytokine expression, potentially due to its ability to repress the expression of the Suppressor of Cytokine signaling 1 (SOCS1) gene[62-64]. However the specific role miR-155 plays during atherosclerosis is still being debated, with a number of studies reporting miR-155 to exert pro-atherogenic effects in ApoE deficient mouse models[65,66]. Targeting miRNAs, which are either regulated by IFN-γ and are known to be involved in atherosclerosis development or regulate the expression of IFN-γ, may provide an excellent therapeutic avenue that allows specific arterial targeted treatment to reduce atherosclerosis development and improve plaque stability without potential consequences from systemic IFN-γ inhibition.


Due to the central role of IFN-γ during atherosclerosis development and plaque stability, along with the expected rise in global rates of CVD-related events, this cytokine represents a promising therapeutic target. Targeting either IFN-γ directly or its signaling pathways in both in vitro and in vivo studies has shown that directed therapies have the potential of reducing atherosclerosis development. However the potential side effects of long term IFN-γ inhibition still needs to be assessed.


P- Reviewer: Atamer A, Lai S S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK

1.  World Health Organisation. Fact Sheet 317. Cardiovascular diseases (CVDs). 2015; Available from: http://www.who.int/mediacentre/factsheets/fs317/en/.  [PubMed]  [DOI]
2.  McLaren JE, Michael DR, Ashlin TG, Ramji DP. Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy. Prog Lipid Res. 2011;50:331-347.  [PubMed]  [DOI]
3.  McLaren JE, Ramji DP. Interferon gamma: a master regulator of atherosclerosis. Cytokine Growth Factor Rev. 2009;20:125-135.  [PubMed]  [DOI]
4.  Dong ZM, Chapman SM, Brown AA, Frenette PS, Hynes RO, Wagner DD. The combined role of P- and E-selectins in atherosclerosis. J Clin Invest. 1998;102:145-152.  [PubMed]  [DOI]
5.  Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L, Beaudet AL. P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J Exp Med. 2000;191:189-194.  [PubMed]  [DOI]
6.  Shih PT, Brennan ML, Vora DK, Territo MC, Strahl D, Elices MJ, Lusis AJ, Berliner JA. Blocking very late antigen-4 integrin decreases leukocyte entry and fatty streak formation in mice fed an atherogenic diet. Circ Res. 1999;84:345-351.  [PubMed]  [DOI]
7.  Lusis AJ. Atherosclerosis. Nature. 2000;407:233-241.  [PubMed]  [DOI]
8.  Li AC, Glass CK. The macrophage foam cell as a target for therapeutic intervention. Nat Med. 2002;8:1235-1242.  [PubMed]  [DOI]
9.  Bobryshev YV. Monocyte recruitment and foam cell formation in atherosclerosis. Micron. 2006;37:208-222.  [PubMed]  [DOI]
10.  Katsuda S, Kaji T. Atherosclerosis and extracellular matrix. J Atheroscler Thromb. 2003;10:267-274.  [PubMed]  [DOI]
11.  Newby AC. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates. Cardiovasc Res. 2006;69:614-624.  [PubMed]  [DOI]
12.  Halvorsen B, Otterdal K, Dahl TB, Skjelland M, Gullestad L, Øie E, Aukrust P. Atherosclerotic plaque stability--what determines the fate of a plaque? Prog Cardiovasc Dis. 2008;51:183-194.  [PubMed]  [DOI]
13.  van Boxel-Dezaire AH, Stark GR. Cell type-specific signaling in response to interferon-gamma. Curr Top Microbiol Immunol. 2007;316:119-154.  [PubMed]  [DOI]
14.  Kleemann R, Zadelaar S, Kooistra T. Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res. 2008;79:360-376.  [PubMed]  [DOI]
15.  Levy DE, Darnell JE. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3:651-662.  [PubMed]  [DOI]
16.  Greenlund AC, Morales MO, Viviano BL, Yan H, Krolewski J, Schreiber RD. Stat recruitment by tyrosine-phosphorylated cytokine receptors: an ordered reversible affinity-driven process. Immunity. 1995;2:677-687.  [PubMed]  [DOI]
17.  Li N, McLaren JE, Michael DR, Clement M, Fielding CA, Ramji DP. ERK is integral to the IFN-γ-mediated activation of STAT1, the expression of key genes implicated in atherosclerosis, and the uptake of modified lipoproteins by human macrophages. J Immunol. 2010;185:3041-3048.  [PubMed]  [DOI]
18.  Whitman SC, Ravisankar P, Elam H, Daugherty A. Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E-/- mice. Am J Pathol. 2000;157:1819-1824.  [PubMed]  [DOI]
19.  Gupta S, Pablo AM, Jiang Xc, Wang N, Tall AR, Schindler C. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest. 1997;99:2752-2761.  [PubMed]  [DOI]
20.  Agrawal S, Febbraio M, Podrez E, Cathcart MK, Stark GR, Chisolm GM. Signal transducer and activator of transcription 1 is required for optimal foam cell formation and atherosclerotic lesion development. Circulation. 2007;115:2939-2947.  [PubMed]  [DOI]
21.  Lim WS, Timmins JM, Seimon TA, Sadler A, Kolodgie FD, Virmani R, Tabas I. Signal transducer and activator of transcription-1 is critical for apoptosis in macrophages subjected to endoplasmic reticulum stress in vitro and in advanced atherosclerotic lesions in vivo. Circulation. 2008;117:940-951.  [PubMed]  [DOI]
22.  Harvey EJ, Ramji DP. Interferon-gamma and atherosclerosis: pro- or anti-atherogenic? Cardiovasc Res. 2005;67:11-20.  [PubMed]  [DOI]
23.  Young JL, Libby P, Schönbeck U. Cytokines in the pathogenesis of atherosclerosis. Thromb Haemost. 2002;88:554-567.  [PubMed]  [DOI]
24.  Buono C, Come CE, Stavrakis G, Maguire GF, Connelly PW, Lichtman AH. Influence of interferon-gamma on the extent and phenotype of diet-induced atherosclerosis in the LDLR-deficient mouse. Arterioscler Thromb Vasc Biol. 2003;23:454-460.  [PubMed]  [DOI]
25.  Charo IF, Taubman MB. Chemokines in the pathogenesis of vascular disease. Circ Res. 2004;95:858-866.  [PubMed]  [DOI]
26.  Valente AJ, Xie JF, Abramova MA, Wenzel UO, Abboud HE, Graves DT. A complex element regulates IFN-gamma-stimulated monocyte chemoattractant protein-1 gene transcription. J Immunol. 1998;161:3719-3728.  [PubMed]  [DOI]
27.  Blankenberg S, Barbaux S, Tiret L. Adhesion molecules and atherosclerosis. Atherosclerosis. 2003;170:191-203.  [PubMed]  [DOI]
28.  Chung HK, Lee IK, Kang H, Suh JM, Kim H, Park KC, Kim DW, Kim YK, Ro HK, Shong M. Statin inhibits interferon-gamma-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells. Exp Mol Med. 2002;34:451-461.  [PubMed]  [DOI]
29.  Lusis AJ, Mar R, Pajukanta P. Genetics of atherosclerosis. Annu Rev Genomics Hum Genet. 2004;5:189-218.  [PubMed]  [DOI]
30.  Panousis CG, Zuckerman SH. Interferon-gamma induces downregulation of Tangier disease gene (ATP-binding-cassette transporter 1) in macrophage-derived foam cells. Arterioscler Thromb Vasc Biol. 2000;20:1565-1571.  [PubMed]  [DOI]
31.  Wuttge DM, Zhou X, Sheikine Y, Wågsäter D, Stemme V, Hedin U, Stemme S, Hansson GK, Sirsjö A. CXCL16/SR-PSOX is an interferon-gamma-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2004;24:750-755.  [PubMed]  [DOI]
32.  Kzhyshkowska J, Neyen C, Gordon S. Role of macrophage scavenger receptors in atherosclerosis. Immunobiology. 2012;217:492-502.  [PubMed]  [DOI]
33.  Canton J, Neculai D, Grinstein S. Scavenger receptors in homeostasis and immunity. Nat Rev Immunol. 2013;13:621-634.  [PubMed]  [DOI]
34.  Barillari G, Albonici L, Incerpi S, Bogetto L, Pistritto G, Volpi A, Ensoli B, Manzari V. Inflammatory cytokines stimulate vascular smooth muscle cells locomotion and growth by enhancing alpha5beta1 integrin expression and function. Atherosclerosis. 2001;154:377-385.  [PubMed]  [DOI]
35.  Inagaki Y, Yamagishi S, Amano S, Okamoto T, Koga K, Makita Z. Interferon-gamma-induced apoptosis and activation of THP-1 macrophages. Life Sci. 2002;71:2499-2508.  [PubMed]  [DOI]
36.  Geng YJ, Wu Q, Muszynski M, Hansson GK, Libby P. Apoptosis of vascular smooth muscle cells induced by in vitro stimulation with interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta. Arterioscler Thromb Vasc Biol. 1996;16:19-27.  [PubMed]  [DOI]
37.  Madamanchi NR, Hakim ZS, Runge MS. Oxidative stress in atherogenesis and arterial thrombosis: the disconnect between cellular studies and clinical outcomes. J Thromb Haemost. 2005;3:254-267.  [PubMed]  [DOI]
38.  Schönbeck U, Mach F, Sukhova GK, Murphy C, Bonnefoy JY, Fabunmi RP, Libby P. Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling in plaque rupture? Circ Res. 1997;81:448-454.  [PubMed]  [DOI]
39.  Weber C, Erl W, Pietsch A, Danesch U, Weber PC. Docosahexaenoic acid selectively attenuates induction of vascular cell adhesion molecule-1 and subsequent monocytic cell adhesion to human endothelial cells stimulated by tumor necrosis factor-alpha. Arterioscler Thromb Vasc Biol. 1995;15:622-628.  [PubMed]  [DOI]
40.  Libby P, Okamoto Y, Rocha VZ, Folco E. Inflammation in atherosclerosis: transition from theory to practice. Circ J. 2010;74:213-220.  [PubMed]  [DOI]
41.  Leitersdorf E. Cholesterol absorption inhibition: filling an unmet need in lipid-lowering management. Eur Heart J. 2001;Supplements 3:E17-E23.  [PubMed]  [DOI]
42.  Li N, Salter RC, Ramji DP. Molecular mechanisms underlying the inhibition of IFN-γ-induced, STAT1-mediated gene transcription in human macrophages by simvastatin and agonists of PPARs and LXRs. J Cell Biochem. 2011;112:675-683.  [PubMed]  [DOI]
43.  Marx N, Kehrle B, Kohlhammer K, Grüb M, Koenig W, Hombach V, Libby P, Plutzky J. PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis. Circ Res. 2002;90:703-710.  [PubMed]  [DOI]
44.  Klementiev B, Enevoldsen MN, Li S, Carlsson R, Liu Y, Issazadeh-Navikas S, Bock E, Berezin V. Antiinflammatory properties of a peptide derived from interleukin-4. Cytokine. 2013;64:112-121.  [PubMed]  [DOI]
45.  Barnholt KE, Kota RS, Aung HH, Rutledge JC. Adenosine blocks IFN-gamma-induced phosphorylation of STAT1 on serine 727 to reduce macrophage activation. J Immunol. 2009;183:6767-6777.  [PubMed]  [DOI]
46.  Lee HS, Chung HJ, Lee HW, Jeong LS, Lee SK. Suppression of inflammation response by a novel A₃ adenosine receptor agonist thio-Cl-IB-MECA through inhibition of Akt and NF-κB signaling. Immunobiology. 2011;216:997-1003.  [PubMed]  [DOI]
47.  Voloshyna I, Hai O, Littlefield MJ, Carsons S, Reiss AB. Resveratrol mediates anti-atherogenic effects on cholesterol flux in human macrophages and endothelium via PPARγ and adenosine. Eur J Pharmacol. 2013;698:299-309.  [PubMed]  [DOI]
48.  Zhang H, Guo C, Zhang A, Fan Y, Gu T, Wu D, Sparatore A, Wang C. Effect of S-aspirin, a novel hydrogen-sulfide-releasing aspirin (ACS14), on atherosclerosis in apoE-deficient mice. Eur J Pharmacol. 2012;697:106-116.  [PubMed]  [DOI]
49.  Zhao ZZ, Wang Z, Li GH, Wang R, Tan JM, Cao X, Suo R, Jiang ZS. Hydrogen sulfide inhibits macrophage-derived foam cell formation. Exp Biol Med (Maywood). 2011;236:169-176.  [PubMed]  [DOI]
50.  Koga M, Kai H, Yasukawa H, Yamamoto T, Kawai Y, Kato S, Kusaba K, Kai M, Egashira K, Kataoka Y. Inhibition of progression and stabilization of plaques by postnatal interferon-gamma function blocking in ApoE-knockout mice. Circ Res. 2007;101:348-356.  [PubMed]  [DOI]
51.  Chen X, Threlkeld SW, Cummings EE, Sadowska GB, Lim YP, Padbury JF, Sharma S, Stonestreet BS. In-vitro validation of cytokine neutralizing antibodies by testing with ovine mononuclear splenocytes. J Comp Pathol. 2013;148:252-258.  [PubMed]  [DOI]
52.  Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11:633-652.  [PubMed]  [DOI]
53.  Gotsman I, Lichtman AH. Targeting interferon-gamma to treat atherosclerosis. Circ Res. 2007;101:333-334.  [PubMed]  [DOI]
54.  Petros RA, DeSimone JM. Strategies in the design of nanoparticles for therapeutic applications. Nat Rev Drug Discov. 2010;9:615-627.  [PubMed]  [DOI]
55.  Baumjohann D, Ansel KM. MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat Rev Immunol. 2013;13:666-678.  [PubMed]  [DOI]
56.  Sonkoly E, Ståhle M, Pivarcsi A. MicroRNAs and immunity: novel players in the regulation of normal immune function and inflammation. Semin Cancer Biol. 2008;18:131-140.  [PubMed]  [DOI]
57.  Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007;27:91-105.  [PubMed]  [DOI]
58.  Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res. 2008;79:581-588.  [PubMed]  [DOI]
59.  Creemers EE, Tijsen AJ, Pinto YM. Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ Res. 2012;110:483-495.  [PubMed]  [DOI]
60.  Quiat D, Olson EN. MicroRNAs in cardiovascular disease: from pathogenesis to prevention and treatment. J Clin Invest. 2013;123:11-18.  [PubMed]  [DOI]
61.  O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA. 2007;104:1604-1609.  [PubMed]  [DOI]
62.  Graff JW, Dickson AM, Clay G, McCaffrey AP, Wilson ME. Identifying functional microRNAs in macrophages with polarized phenotypes. J Biol Chem. 2012;287:21816-21825.  [PubMed]  [DOI]
63.  Androulidaki A, Iliopoulos D, Arranz A, Doxaki C, Schworer S, Zacharioudaki V, Margioris AN, Tsichlis PN, Tsatsanis C. The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity. 2009;31:220-231.  [PubMed]  [DOI]
64.  Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K, Loeb GB, Lee H, Yoshimura A, Rajewsky K. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity. 2009;30:80-91.  [PubMed]  [DOI]
65.  Nazari-Jahantigh M, Wei Y, Noels H, Akhtar S, Zhou Z, Koenen RR, Heyll K, Gremse F, Kiessling F, Grommes J. MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages. J Clin Invest. 2012;122:4190-4202.  [PubMed]  [DOI]
66.  Tian FJ, An LN, Wang GK, Zhu JQ, Li Q, Zhang YY, Zeng A, Zou J, Zhu RF, Han XS. Elevated microRNA-155 promotes foam cell formation by targeting HBP1 in atherogenesis. Cardiovasc Res. 2014;103:100-110.  [PubMed]  [DOI]