Atherosclerosis and interferon-γ: New insights and therapeutic targets

doi:10.1016/j.tcm.2013.06.003

Trends in Cardiovascular Medicine

Volume 24, Issue 1, January 2014, Pages 45-51

https://doi.org/10.1016/j.tcm.2013.06.003 Get rights and content

Abstract

Atherosclerosis is considered to be a chronic inflammatory disease of the arterial wall. Atherogenesis is accompanied by local production and release of inflammatory mediators, for which the macrophage is a major source. The proinflammatory cytokine, interferon (IFN)-γ derived from T cells, is expressed at high levels in atherosclerotic lesions. IFN-γ is the classic macrophage-activating factor, vital for both innate and adaptive immunity. It primes macrophages to produce chemokines and cytotoxic molecules and induces expression of genes that regulate lipid uptake. IFN-γ is a key trigger for the formation and release of reactive oxygen species. IFN-γ has important effects on endothelial cells, promoting expression of adhesion molecules. Atherogenic effects of IFN-γ have been shown in murine models where exogenous administration enhances atherosclerotic lesion formation while knockout of IFN-γ or its receptor reduces lesion size. IFN-γ signaling is largely mediated by a Janus kinase (JAK) to signal transduction and activator of transcription (STAT)1 cytosolic factor pathway. A clear understanding of IFN-γ effects on atherogenesis should enable development of novel targeted interventions for clinical use in the prevention and treatment of atherosclerosis. This review will discuss the actions of the cytokine IFN-γ and its complex effects on cells involved in atherosclerosis.

Introduction

Atherosclerosis involves an ongoing inflammatory response (Libby, 2012). The atherosclerotic plaque consists of large amounts of inflammatory cells, mainly monocytes/macrophages and T lymphocytes. Inflammatory markers are found inside affected vessel walls and in the plasma of patients with atherosclerotic vascular disease (Lind, 2003). Unraveling the details of inflammatory pathways in the vessel wall has direct application in the detection and prevention of cardiovascular disease, and current research is predominantly focused on understanding the impact of this inflammation and how it might be controlled. The pathogenesis of atherosclerosis involves the interplay between cholesterol and cellular secretion of cytokines, a major one being the pleiotropic soluble cytokine interferon-γ (IFN-γ), which is secreted by T lymphocytes and macrophages. IFN-γ is involved in the initiation and modulation of a variety of immune responses, many of which are pro-atherogenic (Billiau and Matthys, 2009). IFN-γ is vital for both innate and adaptive immunity and exerts its effects by activating macrophages, natural killer cells, and B cells. Stimulation of endothelial cells by IFN-γ promotes expression of adhesion molecules. Macrophage activation by IFN-γ leads to the production of other proinflammatory cytokines like tumor necrosis factor (TNF)-α and interleukin (IL)-6, oxygen radicals, and metalloproteinases. Both protein and mRNA for IFN-γ have been detected in human atherosclerotic lesions where it colocalizes with activated major histocompatibility complex (MHC)-II-expressing macrophages (Tedgui and Mallat, 2006). This review will examine the impact of IFN-γ on the cell types within the vessel wall that participate in the atherosclerotic process and the interconnected cascade of events that ultimately form atherosclerotic plaque that is vulnerable to rupture.

Section snippets

IFN-γ signaling

IFNs mediate their effects through activation of intracellular molecular signaling networks, the best characterized of which is the Janus kinase-signal transducer and activator of transcription (JAK)-STAT pathway (Tedgui and Mallat, 2006) (Fig. 1). The IFN-γ receptor is composed of two subunits (IFNGR1 and IFNGR2) that dimerize upon ligand binding leading to transactivation of JAK1 and 2. The activation of JAKs upon cytokine stimulation results in the phosphorylation of the intracellular domain

The role of IFN-γ in atherosclerosis

IFN-γ affects cholesterol accumulation in monocytes/macrophages, induces foam cell formation, and participates in adaptive T-helper type 1 (Th1)-specific immune response, atherosclerotic plaque formation, and rupture. CD4⁺ T lymphocytes in atherosclerotic lesions are predominately Th1 cells. Through IFN-γ production, Th1-type cells stimulate macrophages leading to production of proinflammatory cytokines and vasoactive molecules. Th1 bias drives increased atherosclerosis in mice and recent

New therapeutic targets

Recent findings point to an important immunosuppressive role for the endogenous autacoid adenosine in macrophage-mediated inflammation. Macrophages have been reported to express all four subtypes of the adenosine receptor: A1, A2A, A2B, and A3. Ligation of one or more of these receptors suppresses the production of proinflammatory factors, stimulates expression of reverse cholesterol transport proteins, and inhibits macrophage foam cell formation.

Lee et al. (2011) demonstrated that adenosine A3

Conclusions

IFN-γ is a Th1 cytokine with well-documented atheroma-promoting properties. IFN-γ has multiple effects on all stages of atherogenesis, and there has been progress in understanding the impact of this cytokine on signaling pathways that ultimately lead to plaque development and maturation. In early phases of atherosclerosis, IFN-γ fosters adhesion molecule release from endothelial cells and is a crucial regulator of SMC proliferation. In later stages, IFN-γ can create plaque vulnerability via

Acknowledgments

This work was supported by the Elizabeth Daniell Research Fund and by NIH/NCCAM Grant R21AT007032-01A1.

References (48)

A. Billiau et al.
Interferon-gamma: a historical perspective
Cytokine and Growth Factor Reviews
(2009)
E.Y. Chung et al.
Resveratrol down-regulates interferon-γ-inducible inflammatory genes in macrophages: molecular mechanism via decreased STAT-1 activation
Journal of Nutritional Biochemistry
(2011)
X.R. Hao et al.
IFN-gamma down-regulates ABCA1 expression by inhibiting LXRalpha in a JAK/STAT signaling pathway-dependent manner
Atherosclerosis
(2009)
Y. Inagaki et al.
Interferon-gamma-induced apoptosis and activation of THP-1 macrophages
Life Sciences
(2002)
J. Kzhyshkowska et al.
Role of macrophage scavenger receptors in atherosclerosis
Immunobiology
(2012)
H.S. Lee et al.
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)
L. Lind
Circulating markers of inflammation and atherosclerosis
Atherosclerosis
(2003)
J.E. McLaren et al.
Interferon gamma: a master regulator of atheroslerosis
Cytokine and Growth Factor Reviews
(2009)
K.J. Moore et al.
Macrophages in the pathogenesis of atherosclerosis
Cell
(2011)
A.B. Reiss et al.
Immune complexes and IFN-gamma decrease cholesterol 27-hydroxylase in human arterial endothelium and macrophages
Journal of Lipid Research
(2001)

G. Rimbach et al.

Macrophages stimulated with IFN-gamma activate NF-kappa B and induce MCP-1 gene expression in primary human endothelial cells

Molecular Cell Biology Research Communications

(2000)

L. Varinou et al.

Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-gamma-dependent innate immunity

Immunity

(2003)

I. Voloshyna et al.

The ABC transporters in lipid flux and atherosclerosis

Progress in Lipid Research

(2011)

I. Voloshyna et al.

Resveratrol mediates anti-atherogenic effects on cholesterol flux in human macrophages and endothelium via PPAR-γ and adenosine

European Journal of Pharmacology

(2013)

D. Wågsäter et al.

The chemokine and scavenger receptor CXCL16/SR-PSOX is expressed in human vascular smooth muscle cells and is induced by interferon gamma

Biochemical and Biophysical Research Communications

(2004)

S.C. Whitman et al.

Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E−/− mice

American Journal of Pathology

(2000)

E.P. Amento et al.

Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells

Arteriosclerosis Thrombosis and Vascular Biology

(1991)

B.M. Azari et al.

Transcription and translation of human F11R gene are required for an initial step of atherogenesis induced by inflammatory cytokines

Journal of Translational Medicine

(2011)

K.E. Barnholt et al.

Adenosine blocks IFN-gamma-induced phosphorylation of STAT1 on serine 727 to reduce macrophage activation

Journal of Immunology

(2009)

M.C. Clarke et al.

Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis

Nature Medicine

(2006)

G.J. Dusting et al.

Mechanisms for suppressing NADPH oxidase in the vascular wall

Memorias do Instituto Oswaldo Cruz

(2005)

T. Grewal et al.

Identification of a gamma-interferon-responsive element in the promoter of the human macrophage scavenger receptor A gene

Arteriosclerosis Thrombosis and Vascular Biology

(2001)

D.D. Heistad et al.

Novel aspects of oxidative stress in cardiovascular diseases

Circulation Journal

(2009)

T. Heitzer et al.

Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease

Circulation

(2001)

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Review articleAtherosclerosis and interferon-γ: New insights and therapeutic targets