An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist

Aksentijevich, Ivona; Masters, Seth L.; Ferguson, Polly J.; Dancey, Paul; Frenkel, Joost; Royen-Kerkhoff, Annet van; Laxer, R. M.; Tedgård, Ulf; Cowen, Edward W.; Pham, Tuyet‐Hang; Booty, Matthew G.; Estes, Jacob D.; Sandler, Netanya G.; Plass, Nicole; Stone, Deborah L.; Turner, Maria L.; Hill, Suvimol; Butman, John A.; Schneider, Rayfel; Babyn, Paul; El‐Shanti, Hatem; Pope, Elena; Barron, Karyl S.; Bing, Xinyu; Laurence, Arian; Lee, Chyi‐Chia Richard; Chapelle, Dawn; Clarke, Gillian I.; Ohson, Kamal; Nicholson, Marc; Gadina, Massimo; Yang, Barbara; Korman, Benjamin; Gregersen, Peter K.; Hagen, P. Martin van; Hak, A. Elisabeth; Huizing, Marjan; Rahman, Proton; Douek, Daniel C.; Remmers, Elaine F.; Kastner, Daniel L.; Goldbach‐Mansky, Raphaela

doi:10.1056/nejmoa0807865

Cited by 887 publications

(906 citation statements)

References 36 publications

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“…• Pro-inflammatory mediators dominate during the early hours • Anti-inflammatory cytokines such as IL-10 are later secreted • Regular muscle work has been found to dampen systemic inflammation polymorphism, which occurs in a significant proportion of type 2 diabetic patients, is part of a group of diseases of IL-1RA deficiency that also includes rare mutations in IL1RN that lead to severe multisystem inflammatory syndromes that are highly responsive to IL-1RA treatment [86]. No clear effects on insulin sensitivity or beta cell function were observed after administration of recombinant TNF-α inhibitors despite a decrease in systemic levels of proinflammatory immune mediators [87], except for some cases of concomitant hypoglycaemia [88].…”

Section: Lessons From Immune Intervention Trialsmentioning

confidence: 99%

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

Kolb¹,

2009

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The recent major increase in the global incidence of type 2 diabetes suggests that most cases of this disease are caused by changes in environment and lifestyle. All major risk factors for type 2 diabetes (overnutrition, low dietary fibre, sedentary lifestyle, sleep deprivation and depression) have been found to induce local or systemic low-grade inflammation that is usually transient or milder in individuals not at risk for type 2 diabetes. By contrast, inflammatory responses to lifestyle factors are more pronounced and prolonged in individuals at risk of type 2 diabetes and appear to occur also in the pancreatic islets. Chronic low-grade inflammation will eventually lead to overt diabetes if counter-regulatory circuits to inflammation and metabolic stress are compromised because of a genetic and/or epigenetic predisposition. Hence, it is not the lifestyle change per se but a deficient counter-regulatory response in predisposed individuals which is crucial to disease pathogenesis. Novel approaches of intervention may target these deficient defence mechanisms.

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Section: Lessons From Immune Intervention Trialsmentioning

confidence: 99%

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

Kolb¹,

2009

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“…The balance between IL-1 and IL-1Ra seems crucial in inflammatory diseases [15][16][17][18]. Although IPF is not primarily an inflammatory disease, IPF is characterized by high levels of inflammatory parameters.…”

Section: Il-1 Receptor Antagonist In Ipfmentioning

confidence: 99%

Genetic variability in the IL1RN gene and the balance between interleukin (IL)-1 receptor agonist and IL-1β in idiopathic pulmonary fibrosis

Barlo¹,

Moorsel

Korthagen³

et al. 2011

Clinical and Experimental Immunology

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SummaryIdiopathic pulmonary fibrosis (IPF) is a rapidly progressive interstitial lung disease of unknown aetiology. Interleukin (IL)-1b plays an important role in inflammation and has been associated with fibrotic remodelling. We investigated the balance between IL-1b and IL-1 receptor antagonist (IL-1Ra) in bronchoalveolar lavage fluid (BALF) and serum as well as the influence of genetic variability in the IL1B and IL1RN gene on disease susceptibility and cytokine levels. In 77 IPF patients and 349 healthy controls, single nucleotide polymorphisms (SNPs) in the IL1RN and IL1B genes were determined. Serum and BALF IL-1Ra and IL-1b levels were measured using a multiplex suspension bead array system and were correlated with genotypes. Both in serum and BALF a significantly decreased IL-1Ra/IL-1b ratio was found in IPF patients compared to healthy controls. In the IL1RN gene, one SNP was associated with both the susceptibility to IPF and reduced IL-1Ra/IL-1b ratios in BALF. Our results show that genetic variability in the IL1RN gene may play a role in the pathogenesis of IPF and that this role may be more important than thought until recently. The imbalance between IL-1Ra and IL-1b might contribute to a proinflammatory and pro-fibrotic environment in their lungs.

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Section: Introductionmentioning

confidence: 99%

“…IL-1Ra binds to IL-1 receptors without inducing intracellular signals and acts as a natural competitive IL-1 inhibitor [2]. Genetic IL-1Ra deficiency leads to excessive IL-1 signaling and exaggerated inflammatory responses in several animal models and in humans [1,[3][4][5][6][7][8][9].IL-1β has been proposed as an important mediator in the pathophysiology of hepatic diseases. Indeed, a significant increase of circulating IL-1β levels has been reported in patients with fulminant hepatic failure and chronic liver diseases [10][11][12][13].…”

mentioning

confidence: 99%

Mice deficient in hepatocyte‐specific IL‐1Ra show delayed resolution of concanavalin A‐induced hepatitis

et al. 2012

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Interleukin-1 receptor antagonist (IL-1Ra) is a specific IL-1 inhibitor that possesses antiinflammatory activities. Several studies in human and mouse suggested a protective role for IL-1Ra in liver inflammation, and we previously demonstrated that hepatocytes produce high levels of IL-1Ra in response to inflammatory challenge in vitro and in vivo. In the present study, we investigated the production and the biological function of hepatocytederived IL-1Ra in concanavalin A (ConA)-induced hepatitis in mice. We show that the injured liver produces large amounts of IL-1Ra and that secreted and intracellular IL-1Ra isoforms are produced with different kinetics during the course of hepatitis. By using hepatocyte-specific IL-1Ra-deficient mice (IL-1Ra H ), we demonstrate that hepatocytes represent the major cellular source of local IL-1Ra. Most interestingly, hepatic necrosis and inflammation were increased in IL-1Ra H as compared with wild-type mice during the late phase of the disease, leading to a delayed resolution of hepatitis in IL-1Ra H mice. In conclusion, our results show that the local production of IL-1Ra by hepatocytes contributes to the resolution of hepatitis.Keywords: Cytokine r IL-1 inhibitor r Inflammation r Liver r Necrosis Supporting Information available online IntroductionInterleukin-1β (IL-1β) is a prototypic pro-inflammatory cytokine playing an important role in acute and chronic inflammatory processes and in some autoimmune diseases [1]. The biological activities of IL-1β are tightly controlled by different natural inhibitors, including membrane-bound and soluble IL-1 receptors, Correspondence: Prof. Cem Gabay e-mail: cem.gabay@hcuge.ch and IL-1 receptor antagonist (IL-1Ra) [1]. IL-1Ra binds to IL-1 receptors without inducing intracellular signals and acts as a natural competitive IL-1 inhibitor [2]. Genetic IL-1Ra deficiency leads to excessive IL-1 signaling and exaggerated inflammatory responses in several animal models and in humans [1,[3][4][5][6][7][8][9].IL-1β has been proposed as an important mediator in the pathophysiology of hepatic diseases. Indeed, a significant increase of circulating IL-1β levels has been reported in patients with fulminant hepatic failure and chronic liver diseases [10][11][12][13]. Increased serum levels of IL-1β were also observed in an experimental model of immune-mediated hepatitis induced by concanavalin-A (ConA) injection in mice [14]. By using the same experimental model,www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1294-1303 Innate immunity 1295 mice lacking functional caspase-1, an enzyme involved in IL-1β and IL-18 processing, were resistant to hepatitis [15]. Interestingly, Sekiyama et al. [12] observed elevated IL-1Ra levels in the circulation of patients with fulminant hepatic failure and acute hepatitis, and found that the IL-1Ra/IL-1β ratio was significantly increased in patients who survived. In liver biopsy specimens from patients with chronic hepatitis, IL-1Ra/IL-1β messenger ribonucleic acid (mRNA) ratio were inversely correlated with disease se...

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An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist

Abstract: Background-Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin

Cited by 887 publications

References 36 publications

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

Genetic variability in the IL1RN gene and the balance between interleukin (IL)-1 receptor agonist and IL-1β in idiopathic pulmonary fibrosis

Mice deficient in hepatocyte‐specific IL‐1Ra show delayed resolution of concanavalin A‐induced hepatitis

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