Epstein-Barr Virus-Induced Gene-3 Is Expressed in Human Atheroma Plaques

Kempe, Sybille; Heinz, Philipp; Kókai, Enikö; Devergne, Odile; Marx, Nikolaus; Wirth, Thomas

doi:10.2353/ajpath.2009.080752

Cited by 61 publications

(66 citation statements)

References 52 publications

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“…However, according to recent reports, EBI3 is also expressed in other cell types, including intestinal epithelium and aortic smooth muscle cells (36,37). Our results suggested that epidermal keratinocytes as well as Treg express EBI3, and this expression was decreased in the SSc skin.…”

Section: Discussionsupporting

confidence: 43%

EBI3 Downregulation Contributes to Type I Collagen Overexpression in Scleroderma Skin

Kudo

Wang

Jinnin

et al. 2015

The Journal of Immunology

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IL-12 family cytokines are implicated in the pathogenesis of various autoimmune diseases, but their role in the regulation of extracellular matrix expression and its contribution to the phenotype of systemic sclerosis (SSc) remain to be elucidated. Among the IL-12 family members, IL-35 decreases type I collagen expression in cultured dermal fibroblasts. IL-35 consists of p35 and EBI3 subunits, and EBI3 alone could downregulate the protein and mRNA expression of type I or type III collagen in the presence or absence of TGF-β costimulation. We found that collagen mRNA stability was reduced by EBI3 via the induction of miR-4500. The IL-35 levels in the sera or on the surface of T cells were not altered in SSc patients, while EBI3 expression was decreased in the keratinocytes of the epidermis and regulatory T cells of the dermis in SSc skin compared with normal skin, which may induce collagen synthesis in SSc dermal fibroblasts. We also found that gp130, the EBI3 receptor, was expressed in both normal and SSc fibroblasts. Moreover, we revealed that EBI3 supplementation by injection into the skin improves mice skin fibrosis. Decreased EBI3 in SSc skin may contribute to an increase in collagen accumulation and skin fibrosis. Clarifying the mechanism regulating the extracellular matrix expression by EBI3 in SSc skin may lead to better understanding of this disease and new therapeutic strategies using ointment or microinjection of the subunit.

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Section: Discussionsupporting

confidence: 43%

EBI3 Downregulation Contributes to Type I Collagen Overexpression in Scleroderma Skin

Kudo

Wang

Jinnin

et al. 2015

The Journal of Immunology

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“…*, p Յ 0.05; **, p Յ 0.005; ***, p Յ 0.0005; NS, not significant. addition, strong co-expression of Ebi3 and p35 in smooth muscle cells, endothelial cells, and macrophages of advanced lesions in patients with symptomatic carotid plaques (40) and positive correlation of plasma IL-35 levels with the left ventricular ejection fraction in a large number of CAD patients (41) has led to the hypothesis that IL-35 may be involved in amelioration of atherosclerosis and improved prognosis in CAD (42). Here we provide strong evidence that IL-35 can play a key role in the amelioration of plaque burden in atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

Park¹,

Huang²,

Jankowska‐Gan

et al. 2016

Journal of Biological Chemistry

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We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe ؊/؊ mouse model. We have also shown sensitization of Apoe ؊/؊ mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr ؊/؊ mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the ␣1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr ؊/؊ mice, suggesting future courses of experimentation for the characterization of such epitopes.Atherosclerosis underlies coronary artery disease (CAD) 3 and stroke, major global causes of death (1), and is a chronic inflammatory disease that is modulated by both innate and adaptive immune pathways. It is increasingly accepted that autoimmunity constitutes some portion of the pathological processes underlying atherosclerosis, with oxidized LDLs, native lipoproteins, and heat shock proteins identified as autoantigens involved in atherogenesis (1-8). Recognition of the autoimmune aspects of atherosclerosis has suggested the possibility of employing immunomodulatory approaches to ameliorate symptoms. That such an approach is feasible has been borne out in studies in which blockage of T cells reactive to native lipoprotein ApoB100 (4) or mucosal or subcutaneous immunization with HSP65 (9, 10), oxidized LDL (11), native ␤2-glycoprotein I (12), or apolipoprotein B-100 peptide (13, 14) have been shown to be atheroprotective. Collagens can compose up to 60% of the total protein content in atherosclerotic plaques (15) and stimulate the growth and inflammation of atheromas (16). We have shown previously that interleukin 17-dependent autoimmunity to type V collagen col(V)) is a consistent feature of atherosclerosis in advanced CAD in humans and in Apoe Ϫ/Ϫ mice on a high-fat diet (17). Moreover, the same study provided evidence of a causative role for col(V) autoimmunity in the pathogenesis of atherosclerosis because sensitization of Apoe Ϫ/Ϫ mice on normal chow to col(V) has been shown to markedly increase the ...

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“…IL-27 is expressed in atherosclerotic plaques 93 , and its role in atherosclerosis has been reported in cultured cells, animal models and coronary patients with inconsistent findings. In IL-27-deficient (Ldlr 94 .…”

Section: Il-27mentioning

confidence: 99%

“…On the other hand, the expression of IL-35 increased significantly in ApoE −/− mice with attenuated plaque. In fact, coexpression of the two subunits of IL-35 has been demonstrated in human advanced atherosclerotic plaque 93 . Decreased levels of IL-35 have been reported in patients with acute coronary syndrome (unstable angina pectoris and acute myocardial infarction) compared to a chest pain syndrome group; IL-35 levels also positively correlated with left ventricular ejection fraction whose reduction is associated with heart failure 109 .…”

Section: Il-35mentioning

confidence: 99%

Innate Immunity in Coronary Disease. The Role of Interleukin-12 Cytokine Family in Atherosclerosis

Posadas-Sánchez

Vargas‐Alarcón

2018

RIC

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Atherosclerosis is a chronic, progressive, and multifactorial disease modulated by genetic and environmental factors. In recent years, the paradigm that explained atherosclerosis as resulting from a complex interaction between factors not accessible to medical intervention, and modifiable risk factors has changed. In this paradigm, alterations in lipid metabolism were the pivotal concept of atherosclerosis as a chronic degenerative disease. In the last years, an increasing number of observations have shown that the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall significantly influence atherosclerosis. Currently, it is well recognized that the pathogenesis of atherosclerosis and its complications involves the inflammatory process, which includes the participation of several cytokines. Besides the classic cytokines involved in this process, the role of the interleukin-12 (IL-12) family has been recently demonstrated. This review describes our current understanding about the role of the family of IL-12 in atherosclerosis considering the participation of the genes that encode these cytokines in the genetic susceptibility to developing this disease.

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Epstein-Barr Virus-Induced Gene-3 Is Expressed in Human Atheroma Plaques

Cited by 61 publications

References 52 publications

EBI3 Downregulation Contributes to Type I Collagen Overexpression in Scleroderma Skin

EBI3 Downregulation Contributes to Type I Collagen Overexpression in Scleroderma Skin

Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

Innate Immunity in Coronary Disease. The Role of Interleukin-12 Cytokine Family in Atherosclerosis

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