Involvement of interleukin-6 in atherosclerosis but not in the prevention of fatty streak formation by 17β-estradiol in apolipoprotein E-deficient mice

Elhage, Rima; Clamens, Simone; Besnard, Sandrine; Mallat, Ziad; Tedgui, Alain; Arnal, Jean‐François; Maret, Arlette; Bayard, Françis

doi:10.1016/s0021-9150(00)00682-1

Cited by 114 publications

(83 citation statements)

References 30 publications

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“…Tietge, unpublished observations). Therefore, differences only emerge when the turnover rate of lipoproteins is decreased in genetic models like the ApoE Ϫ/Ϫ mice may show enhanced plaque formation, 12 we hardly observed any plaque formation in 1-yearold male IL-6 Ϫ/Ϫ mice being fed normal rodent chow. However, in the ApoE Ϫ/Ϫ model, IL-6 deficiency resulted in enhanced atherosclerosis and also provided evidence that IL-6 may be a major regulator of normal vessel development.…”

Section: Schieffer Et Al Interleukin-6 In Experimental Atherosclerosimentioning

confidence: 57%

Impact of Interleukin-6 on Plaque Development and Morphology in Experimental Atherosclerosis

Schieffer

Selle²,

Hilfiker³

et al. 2004

Circulation

286

189

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Background— Vascular lipid accumulation and inflammation are hallmarks of atherosclerosis and perpetuate atherosclerotic plaque development. Mediators of inflammation, ie, interleukin (IL)-6, are elevated in patients with acute coronary syndromes and may contribute to the exacerbation of atherosclerosis. Methods and Results— To assess the role of IL-6 in atherosclerosis, ApoE −/− – IL-6 −/− double-knockout mice were generated, fed a normal chow diet, and housed for 53±4 weeks. Mortality and blood pressure were unaltered. However, serum cholesterol levels and subsequent atherosclerotic lesion formation (oil red O stain) were significantly increased in ApoE −/− – IL-6 −/− mice compared with ApoE −/− , wild-type (WT), and IL-6 −/− mice. Plaques of ApoE −/− – IL-6 −/− mice showed significantly reduced transcript and protein levels of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, collagen I and V, and lysyl oxidase (by reverse transcriptase-polymerase chain reaction and immunohistochemistry). Recruitment of macrophages and leukocytes (Mac3- and CD45-positive staining) into the atherosclerotic lesion was significantly reduced in ApoE −/− – IL-6 −/− mice. The transcript and serum protein (ELISA) levels of IL-10 were significantly reduced. Conclusions— Thus, a lifetime IL-6 deficiency enhances atherosclerotic plaque formation in ApoE K −/− – IL-6 −/− mice and leads to maladaptive vascular developmental processes. These observations are consistent with the notion that baseline levels of IL-6 are required to modulate lipid homeostasis, vascular remodeling, and plaque inflammation in atherosclerosis.

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Section: Schieffer Et Al Interleukin-6 In Experimental Atherosclerosimentioning

confidence: 57%

Impact of Interleukin-6 on Plaque Development and Morphology in Experimental Atherosclerosis

Schieffer

Selle²,

Hilfiker³

et al. 2004

Circulation

286

189

View full text Add to dashboard Cite

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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).…”

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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“…Studying IL-6 role in atherogenesis in IL-6 deficent mice Elhage et al [70] surprisingly showed how early lesion formation was not affected by the absence of IL-6. In contrast, when atherosclerosis was examined at 1 year of age, the atherosclerotic lesions were larger in the apoE -/-IL-6 -deficient mice compared with controls, making IL-6 an antiatherogenic factor.…”

Section: Interleukin-6 (Il-6)mentioning

confidence: 99%

Effects of Physical Exercise on Inflammatory Markers of Atherosclerosis

Pinto¹,

Raimondo

Tuttolomondo³

et al. 2012

CPD

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Abstract:It is well established that physically fit individuals have a reduced risk of developing CVD (cardiovascular disease) and other age-related chronic disorders. Regular exercise is an established therapeutic intervention with an enormous range of benefits. Chronic low-grade systemic inflammation may be involved in atherosclerosis, diabetes and in pathogenesis of several chronic pathological conditions; recent findings confirm that physical activity induces an increase in the systemic levels of a number of cytokines and chemokines with anti-inflammatory properties. The possibility that regular physical exercise exerts anti-inflammation activity, being the interaction between contracting muscle and the other tissues and the circulating cells mediated through signals transmitted by "myokines" produced with muscle contractions. To date the list of myokines includes IL-6, IL-8, and IL-15. During muscle contractions are also released IL1receptor antagonis and sTNF-R, molecules that contribute to provide anti-inflammatory actions.Nevertheless discrepancies, analysis of available researches seem to confirm the efficacy of regular physical training as a nonpharmacological therapy having target chronic low-grade inflammation. Given this, physical exercise could be considerate a useful weapon against local vascular and systemic inflammation in atherosclerosis. Several mechanisms explain the positive effect of chronic exercise, nevertheless, these mechanisms do not fully enlighten all pathways by which exercise can decrease inflammation and endothelial dysfunction, and hence modulate the progression of the underlying disease progress.

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Involvement of interleukin-6 in atherosclerosis but not in the prevention of fatty streak formation by 17β-estradiol in apolipoprotein E-deficient mice

Cited by 114 publications

References 30 publications

Impact of Interleukin-6 on Plaque Development and Morphology in Experimental Atherosclerosis

Impact of Interleukin-6 on Plaque Development and Morphology in Experimental Atherosclerosis

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

Effects of Physical Exercise on Inflammatory Markers of Atherosclerosis

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