Attenuation of Experimental Atherosclerosis by Interleukin-19

Ellison, Stephen; Gabunia, Khatuna; Kelemen, Sheri E.; England, Ross N.; Scalia, Rosario; Richards, James M.; Orr, A. Wayne; Traylor, James; Rogers, Thomas J.; Cornwell, William D.; Berglund, Lisa M.; Gonçalves, Isabel; Gomez, Maria F.; Autieri, Michael V.

doi:10.1161/atvbaha.113.301521

Cited by 54 publications

(67 citation statements)

References 42 publications

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“…To our knowledge, the secretory function of blood monocytes might be attenuated after they have infiltrated into endothelial tissues and becomed foam cells. Moreover, IL-37 was detected in intimal and medial SMCs in human arteries with atherosclerosis but not in normal arteries, which is consistent with the Th2-cytokine IL-9, the expression of which has not been found in immune cells or normal SMCs but has been show in injured SMCs [37]. …”

Section: Discussionmentioning

confidence: 54%

Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability

Liu

Lin

et al. 2018

Cell Physiol Biochem

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Background/Aims: Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved. Methods: IL-37 expression in human atherosclerotic plaques was detected by immunohistochemical staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Oil Red O staining was used to measure the size of plaques. Cell apoptosis in vitro and in vivo was tested by flow cytometric analysis and terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) staining, respectively. Protein expression levels of IL-37, IL-18Rα and p-Smad3 were measured by Weston blotting. Results: Immunohistochemical staining revealed that IL-37 was highly expressed in human atherosclerotic plaques. Intracellular cytokine staining revealed that infiltrated CD4⁺ T lymphocytes and vascular smooth muscle cells (VSMCs), but not macrophages, were the major sources of IL-37. Mice that overexpressed IL-37 exhibited significant improvements in their atherosclerotic burden, as demonstrated by reduced plaque size, increased collagen levels, and reduced numbers of apoptotic cells in vivo. Subsequently, mechanistic studies showed that IL-37 played an anti-atherosclerotic role, at least partially, through reducing inflammation by promoting the differentiation of the T helper cell anti-inflammatory phenotype, and through increasing plaque stability by decreasing matrix metalloproteinase (MMP)-2/13-mediated degradation of collagen and inhibiting VSMCs apoptosis. Conclusion: IL-37 may be a novel potential therapeutic target in patients with atherosclerotic heart disease.

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Section: Discussionmentioning

confidence: 54%

Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability

Liu

Lin

et al. 2018

Cell Physiol Biochem

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“…73 IL-19 decreased atherosclerosis in Ldlr -/-or Apoe -/-mice, and the expression of the Th1 markers T-bet and IFN-γ was reduced in splenocytes from mice injected with IL-19. 74 Several studies support a protective role of IL-5-producing Th2 cells in atherosclerosis. MDA-modified LDL vaccination of Apoe -/-mice reduced atherosclerosis via secretion of IL-5 and increased production of anti-oxLDL IgM antibodies, whereas IL-5 deficiency inhibited the protective effect of vaccination by blocking the production of anti-oxLDL antibodies.…”

Section: Th1 Cellsmentioning

confidence: 99%

Adaptive (T and B Cells) Immunity and Control by Dendritic Cells in Atherosclerosis

Ait‐Oufella

Sage

Mallat

et al. 2014

Circulation Research

173

121

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14 Altogether, these early observations on the presence of T cells in human and in mouse atherosclerotic plaques remained associative and did not show causation.Subsequent studies using animal models of atherosclerosis, especially Apoe -/-or Ldlr -/-mice, in which human-like atherosclerotic lesions develop spontaneously or in response to high-fat diet, provided more direct evidence for the participation of adaptive immunity in atherogenesis. Apoe -/-or Ldlr -/-mice crossed with immunodeficient mice that lack the V(D)J recombination-activating protein 1 (Rag1) or have a severe combined immunodeficiency mutation (SCID; scid/scid mice) show, in general, reduced development of atherosclerotic lesions when fed a chow diet.5 These immunodeficient mice that lack both T and conventional B cells are not particularly informative on the role of specific T-and B-cell subpopulations that can be either pro-or antiatherogenic (see below). One study found no difference between immune-competent and immune-deficient mice fed a high-fat diet. 15The specific role of T cells was substantiated by experiments showing that the transfer of CD4 + T cells into scid/scid/ Apoe -/-mice fully reversed the atheroprotection provided by T/B deficiency. 16 However, when the effect of CD4 + T cells was evaluated in CD4-deficient Apoe -/-mice, contrasting results were reported. Female CD4 -/-Apoe -/-mice exhibited markedly larger lesions in the descending thoracic aorta, but no effect was observed in the aortic root when compared with wild-type (WT) Apoe -/-mice. 17 Intriguingly, in a subsequent study using the same CD4/Apoe double knockout mice, atherosclerosis in the aortic sinus was reduced, but the authors made no mention of the effect of CD4 + T-cell deficiency on atherosclerosis in the aorta.18 Of note, in both studies, the CD8 + cell population and the titers of anti-malondialdehyde (MDA)-oxidized lowdensity lipoprotein (oxLDL) IgM antibodies were increased. CD8 + T cells were recently shown to promote the development of vulnerable atherosclerotic plaques, 19 whereas natural antioxLDL IgM autoantibodies are atheroprotective 20 (see below). The specific recognition of peptide antigens presented by MHC molecules triggers TCR signaling, but costimulatory and coinhibitory receptors on T cells direct T-cell function and determine T-cell fate. These cosignaling molecules are members of the immunoglobulin superfamily, including B7 (CD80/86), CD28, programmed cell death 1 and cytotoxic T-lymphocyte antigen 4 (CTLA4), and the tumor necrosis factor (TNF) receptor superfamily, including CD40, CD27, OX40, and CD137. Experiments aimed at investigating the role of cosignaling molecules provided further evidence for a role of T cells in atherogenesis 21,22 (see Functional roles for DCs in atherosclerosis section of this article). For example, blockade of the OX40-OX40L interaction by anti-OX40L antibody treatment in Ldlr -/-23 or Apoe -/-24 mice reduced atherosclerosis. Yet, blockade of T-cell activation was accompanied by an enhanced B-1 cell activity an...

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“…Curiously, psoriasis -a skin condition characterized by elevated expression of IL-20 subfamily cytokines -is also associated with an increased risk of atherosclerosis 181 . Indeed, IL-19 and IL-20 are expressed in artery plaques found in patients with atherosclerosis 182,183 . IL-20RA-IL-20RB, the receptor complex for IL-19 and IL-20, is also expressed on endothelial cells of atherosclerotic lesions 183 .…”

Section: Il-20 Subfamily Cytokines In Metabolismmentioning

confidence: 99%

The IL-20 subfamily of cytokines — from host defence to tissue homeostasis

Rutz¹,

Wang²,

Ouyang³

2014

Nat Rev Immunol

314

326

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The interleukin-20 (IL-20) subfamily of cytokines comprises IL-19, IL-20, IL-22, IL-24 and IL-26. These cytokines are all members of the larger IL-10 family, but have been grouped together to form the IL-20 subfamily based on their usage of common receptor subunits and similarities in their target-cell profiles and biological functions. Members of the IL-20 subfamily facilitate the communication between leukocytes and epithelial cells, thereby enhancing innate defence mechanisms and tissue repair processes at epithelial surfaces. In this Review, we describe the cellular sources and targets of the IL-20 subfamily cytokines, and we detail how their expression is regulated. Much of our understanding of the unique biology of this group of cytokines is still based on IL-22, which is the most studied member of the IL-20 subfamily. Nevertheless, we attempt a broader discussion of the emerging functions of IL-20 subfamily cytokines in host defence, inflammatory diseases, cancer and metabolism.

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Attenuation of Experimental Atherosclerosis by Interleukin-19

Cited by 54 publications

References 42 publications

Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability

Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability

Adaptive (T and B Cells) Immunity and Control by Dendritic Cells in Atherosclerosis

The IL-20 subfamily of cytokines — from host defence to tissue homeostasis

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