The Role of Interleukin-4 and Interleukin-12 in the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice

Davenport, Piers; Tipping, Peter G.

doi:10.1016/s0002-9440(10)63471-2

Cited by 391 publications

(315 citation statements)

References 48 publications

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“…Accumulation of T cells and macrophages in atherosclerotic plaques and the formation of antibodies directed against plaque proteins suggests that adaptive immunity contributes to the development of atherosclerosis [30]. Zhou and Hansson demonstrated the presence of CD22 positive B cells and IgM in the aortic root lesions of ApoE -/-mice [31].…”

Section: Discussionmentioning

confidence: 99%

Accelerated atherosclerosis in ApoE deficient lupus mouse models

Choudhury

Kang

et al. 2008

Clinical Immunology

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The accelerated development of atherosclerosis with increased risk of cardiovascular disease in systemic lupus erythematosus (SLE) patients is not well understood. An appropriate mouse model would greatly help to understand the mechanisms of this association. We have therefore combined the ApoE -/-model of atherosclerosis with three different murine models of SLE. We found that induction of cGVH in B6.ApoE -/-mice, breeding a Fas null gene onto these B6/lpr.ApoE -/-mice, and breeding the ApoE -/-defect onto MRL/lpr mice all caused a modest increase of atherosclerosis at 24 weeks of age compared to B6.ApoE -/-controls. B cells in B6.ApoE -/-mice had certain phenotypic differences compared to congenic C57BL/6 mice, as indicated by high expression of MHC II, Fas, CD86, and by increased number of cells bearing marginal-zone phenotype. Furthermore, B6ApoE -/-mice had significant titers of anti-oxLDL and anti-cardiolipin autoantibodies compared to their B6 counterparts. Our studies also indicate that, following induction of cGVH, marginal zone B cells in B6.ApoE -/-are depleted, and there is considerable increase in anti-oxLDL and anticardiolipin abs along with secretion of lupus-specific autoantibodies, such as anti-dsDNA and antichromatin abs. Histological sections showed that cGVH and/or Fas deficiency could exacerbate atherosclerosis. The production of anti-oxLDL and anti-cardiolipin in ApoE -/-mice was also increased. These observations define a connection between induction of lupus-like symptoms and development of severe atherosclerosis in apoE deficient lupus mouse models.

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Section: Discussionmentioning

confidence: 99%

Accelerated atherosclerosis in ApoE deficient lupus mouse models

Choudhury

Kang

et al. 2008

Clinical Immunology

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“…The effect of IL-6 on atherosclerosis is unclear; whereas administration of recombinant IL-6 increased atherosclerosis, IL-6 deficiency on an E Ϫ/Ϫ background has no effect when mice were killed at 16 weeks of age (25,26). However, IL-6 through IL-6ST mediates the production of IL-12, and the latter when deficient on the E Ϫ/Ϫ background results in decreased atherosclerosis (27). IL-6ST is shared by many cytokines that act through JAK-STAT pathways, including IL-6, IL-11, ciliary neurotrophic factor, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and cardiotrophin-like cytokine (28).…”

Section: Discussionmentioning

confidence: 99%

The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-κB target genes

Wolfrum

Teupser

Tan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Up-regulation of inflammatory responses is considered a driving force of atherosclerotic lesion development. One key regulator of inflammation is the A20 (also called TNF-␣-induced protein 3 or Tnfaip3) gene, which is responsible for NF-B termination and maps to an atherosclerosis susceptibility locus revealed by quantitative trait locus-mapping studies at mouse proximal chromosome 10. In the current study, we examined the role of A20 in atherosclerotic lesion development. At the aortic root lesion size was found to be increased in C57BL/6 (BG) apolipoprotein E-deficient (ApoE ؊/؊ ) mice haploinsufficient for A20, compared with B6 ApoE ؊/؊ controls that expressed A20 normally (60% in males and 23% in females; P < 0.001 and P < 0.05, respectively). In contrast, lesion size was found to be decreased in F 1 (B6؋FVB/N) mice overexpressing A20 by virtue of containing an A20 BAC transgene compared with nontransgenic controls (30% in males, P < 0.001, and 17% in females, P ‫؍‬ 0.02). The increase in lesions in the A20 haploinsufficient mice correlated with increased expression of proatherosclerotic NF-B target genes, such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and macrophage-colony-stimulating factor, and elevated plasma levels of NF-B-driven cytokines. These findings suggest that A20 diminishes atherosclerosis by decreasing NF-B activity, thereby modulating the proinflammatory state associated with lesion development.A therosclerosis is a chronic inflammatory disease influenced by many genes, and mouse models are useful for identifying these genes and determining their mechanisms of action. We previously carried out an intercrosses between atherosclerosissensitive apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) C57BL/6 (B6) and atherosclerosis-resistant ApoE Ϫ/Ϫ FVB mice, and by quantitative trait locus mapping identified an atherosclerosissusceptibility locus on proximal chromosome 10 (1, 2). A candidate gene in this region, A20, encodes a broadly expressed cytoplasmic protein that inhibits both TNF-␣-and IL-1␤/Tolllike receptor (TLR)-induced NF-B activation through mediating the destruction of receptor-interacting serine/threonine protein kinase 1 (RIP) and TNF receptor-associated factor 6 in their respective signaling complexes (3, 4). Up-regulation of NF-B activity leads to increased expression of many genes with established roles in atherosclerosis, including cytokines, chemokines, adhesion molecules, acute phase proteins, and regulators of apoptosis and cell proliferation. NF-B terminates its own activation by inducing the expression of I B␣ and A20. A20-deficient (A20 Ϫ/Ϫ ) mice die prematurely because of cachexia and spontaneous inflammation in several organs. This phenotype correlates with the failure to properly terminate TNF-induced NF-B activity in fibroblasts isolated from A20 Ϫ/Ϫ mice (5). We previously determined that A20 derived from B6 and FVB mice differs in a single amino acid residue (E627A; B6 vs. FVB). We showed this finding to be functionally significant by demonstrating...

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“…IL-18-deficient animals developed reduced atherosclerosis in ApoE knockout [116]. IL-12 has been reported as a pro-atherogenic cytokine [117][118][119][120][121]. Blockade of IL-12 signaling by vaccination attenuates atherosclerosis [122].…”

Section: Inflammatory Cytokines: Agitators Of Inflammatory Milieumentioning

confidence: 99%

Nuclear receptors in macrophages: A link between metabolism and inflammation

Szántó

Röszer

2007

FEBS Letters

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Subclinical inflammation is a candidate etiological factor in the pathogenesis of metabolic syndrome and in the progression of atherosclerosis. A central role for activated macrophages has been elucidated recently as important regulators of the inflammatory process in atherosclerosis. Macrophage differentiation and function can be modulated by a class of transcription factors termed nuclear receptors. These are activated by intermediary products of basic metabolic processes. In this review the contribution of peroxisome proliferator-activated receptors and liver X receptors to macrophage functions in inflammation and lipid metabolism will be discussed in light of their roles in macrophages during atherosclerosis.In the past decade much effort has been made to understand the mechanisms how lipids are handled by macrophages and how inflammation could promote the atherogenic process. Here, we also provide an overview of these two fields.

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The Role of Interleukin-4 and Interleukin-12 in the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice

Cited by 391 publications

References 48 publications

Accelerated atherosclerosis in ApoE deficient lupus mouse models

Accelerated atherosclerosis in ApoE deficient lupus mouse models

The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-κB target genes

Nuclear receptors in macrophages: A link between metabolism and inflammation

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