A Functional Interleukin-1 Receptor Antagonist Polymorphism Influences Atherosclerosis Development  The Interleukin-1.BETA.:Interleukin-1 Receptor Antagonist Balance in Atherosclerosis

Olofsson, Peder S.; Sheikine, Yuri; Jatta, Ken; Ghaderi, Mehran; Samnegård, Ann; Eriksson, Per; Sirsjö, Allan

doi:10.1253/circj.cj-08-1150

Cited by 55 publications

(38 citation statements)

References 45 publications

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“…Supporting this notion, several subsequent studies have also demonstrated Caspase-1 deficiency is protective against murine atherosclerosis (160, 161). Moreover, IL-1β inhibition is known to reduce atherosclerosis in mice deficient in Apoe (162), and elevated IL-1β levels are associated with an increased risk of atherosclerosis in humans (163). These findings all support a model in which the predominant NLRP3-dependent cytokines, IL-1β and IL-18, are central to disease progression.…”

Section: Atherosclerosismentioning

confidence: 57%

The Inflammasomes and Autoinflammatory Syndromes

Broderick

Nardo

Franklin

et al. 2015

Annu. Rev. Pathol. Mech. Dis.

259

196

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Inflammation, a vital response of the immune system to infection and damage to tissues, can be initiated by various germline-encoded innate immune-signaling receptors. Among these, the inflammasomes are critical for activation of the potent proinflammatory interleukin-1 cytokine family. Additionally, inflammasomes can trigger and maintain inflammatory responses aimed toward excess nutrients and the numerous danger signals that appear in a variety of chronic inflammatory diseases. We discuss our understanding of how inflammasomes assemble to trigger caspase-1 activation and subsequent cytokine release, describe how genetic mutations in inflammasome-related genes lead to autoinflammatory syndromes, and review the contribution of inflammasome activation to various pathologies arising from metabolic dysfunction. Insights into the mechanisms that govern inflammasome activation will help in the development of novel therapeutic strategies, not only for managing genetic diseases associated with overactive inflammasomes, but also for treating common metabolic diseases for which effective therapies are currently lacking.

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Section: Atherosclerosismentioning

confidence: 57%

The Inflammasomes and Autoinflammatory Syndromes

Broderick

Nardo

Franklin

et al. 2015

Annu. Rev. Pathol. Mech. Dis.

259

196

View full text Add to dashboard Cite

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“…IL-1␤ levels increase in the arterial plaques, and the levels of IL-1␤ directly correlate with disease severity (27,28). Patients with a polymorphism in the IL-1 receptor antagonist, which increases IL-1␤ production, have increased risk of developing atherosclerosis (29). The role of NAD ϩ and the sirtuins in the development of atherosclerosis has yet to be investigated.…”

Section: Role Of Nad ؉ Sirtuins and Amp-dependent Protein Kinase Imentioning

confidence: 99%

How Metabolism Generates Signals during Innate Immunity and Inflammation

McGettrick

O’Neill

2013

Journal of Biological Chemistry

204

167

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The interplay between immunity, inflammation, and metabolic changes is a growing field of research. Toll-like receptors and NOD-like receptors are families of innate immune receptors, and their role in the human immune response is well documented. Exciting new evidence is emerging with regard to their role in the regulation of metabolism and the activation of inflammatory pathways during the progression of metabolic disorders such as type 2 diabetes and atherosclerosis. The proinflammatory cytokine IL-1␤ appears to play a central role in these disorders. There is also evidence that metabolites such as NAD ؉ (acting via deacetylases such as SIRT1 and SIRT2) and succinate (which regulates hypoxia-inducible factor 1␣) are signals that regulate innate immunity. In addition, the extracellular overproduction of metabolites such as uric acid and cholesterol crystals acts as a signal sensed by NLRP3, leading to the production of IL-1␤. These observations cast new light on the role of metabolism during host defense and inflammation.

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“…For example, the balance between IL-1b and IL-1Ra has been reported to influence atherosclerosis development in human atherosclerotic arteries [22,23]. In addition, reduced levels of IL-1Ra led to aggravation of murine atherosclerosis [23], and patients with polymorphism in the IL-1Ra intron 2, which is known to increase IL-1Ra levels and possibly the IL-1Ra:IL-1b ratio, were associated with reduced coronary atherosclerosis [24]. Although it has been well documented that IL-1b and IL-1Ra play a central role in vascular pathogenesis through modulation of pro-atherogenic action including VSMC proliferation [25], the underlying molecular mechanisms that regulate the balance between the actions of IL-1Ra and IL-1b in atherosclerosis are not clearly understood.…”

Section: Introductionmentioning

confidence: 99%

PPARδ inhibits IL-1β-stimulated proliferation and migration of vascular smooth muscle cells via up-regulation of IL-1Ra

Kim

Hwang

et al. 2010

Cell. Mol. Life Sci.

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Activation of peroxisome proliferator-activated receptor (PPAR) delta by GW501516, a specific PPARdelta ligand, significantly inhibited interleukin (IL)-1beta-induced proliferation and migration of vascular smooth muscle cells (VSMCs). This effect of GW501516 was dependent on transforming growth factor-beta, and was mediated through the up-regulation of IL-1 receptor antagonist. The inhibitory effect of GW501516 on VSMC proliferation was associated with cell cycle arrest at the G1 to S phase transition, which was accompanied by the induction of p21 and p53 along with decreased cyclin-dependent kinase 4 expression. Inhibition of cell migration by GW501516 was associated with the down-regulation of matrix metalloproteinase (MMP)-2 and MMP-9 in IL-1beta-treated VSMCs. Inhibition of extracellular signal-regulated kinase significantly reduced the GW501516-mediated inhibition of IL-1beta-stimulated VSMC proliferation. These results suggest that PPARdelta plays an important role in the pathophysiology of diseases associated with the proliferation and migration of VSMCs.

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A Functional Interleukin-1 Receptor Antagonist Polymorphism Influences Atherosclerosis Development The Interleukin-1.BETA.:Interleukin-1 Receptor Antagonist Balance in Atherosclerosis

Cited by 55 publications

References 45 publications

The Inflammasomes and Autoinflammatory Syndromes

The Inflammasomes and Autoinflammatory Syndromes

How Metabolism Generates Signals during Innate Immunity and Inflammation

PPARδ inhibits IL-1β-stimulated proliferation and migration of vascular smooth muscle cells via up-regulation of IL-1Ra

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