Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein.

Gabay, Cem; Smith, Michael F.; Eidlen, Denise M.; Arend, William P.

doi:10.1172/jci119488

Cited by 285 publications

(215 citation statements)

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“…However, dominant-negative NF-B failed to modify the rosiglitazone-induced enhancement of IL-1Ra secretion in synoviocytes, which demonstrates that this pathway was not primarily involved despite its requirement for cellular activation. Based on previous studies on the human IL-1Ra promoter, one can suggest that rosiglitazone could have affected alternate IL-1-sensitive transacting factors such as CCAAT/enhancer binding proteins or activator protein 1 (60,61). Second, we searched for the possible contribution of PPAR␤/␦, since high-dose rosiglitazone was shown to activate the PPAR-responsive promoter in cells expressing PPAR␤/␦ but not PPAR␥ (19), whereas it inhibited inflammatory genes through activation of the PPAR␤/␦ isotype in macrophages (62).…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Moulin¹,

Bianchi²,

Boyault³

et al. 2005

Arthritis & Rheumatism

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Objective. To study the potency of 2 peroxisome proliferator-activated receptor ␥ (PPAR␥) agonists, 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15-deoxy-PGJ 2 ) and rosiglitazone, to modulate the expression of interleukin-1 receptor antagonist (IL-1Ra) in rat synovial fibroblasts.Methods. Levels of messenger RNA for IL-1Ra and PPAR isotypes (␣, ␤/␦, ␥) were assessed by realtime polymerase chain reaction in rat synovial fibroblasts exposed to 10 ng/ml of IL-1␤. PPAR levels were assessed by Western blotting and secreted IL-1Ra levels by immunoassay. The potency of PPAR␥ agonists and the PPAR␤/␦ agonist GW-501516 on IL-1Ra levels was tested in the range of 1-10 M and at 100 pM, respectively. The contribution of PPAR␥ to the effects of rosiglitazone on IL-1Ra secretion was examined either by its overexpression or by inhibition using wild-type or dominant-negative constructs and the antagonist GW-9662 (10 M), respectively. The dominant-negative strategy was also performed to investigate the possible contribution of PPAR␤/␦ and NF-B activation.Results. IL-1␤-induced IL-1Ra production was increased by 10 M rosiglitazone but was reduced dose-dependently by 15-deoxy-PGJ 2 . Both agonists lowered IL-1␤ secretion, but rosiglitazone alone reduced the imbalance of IL-1␤/IL-1Ra toward basal levels. Enhancement of IL-1␤-induced IL-1Ra production by rosiglitazone was not affected by PPAR␥ overexpression or by its inhibition with dominant-negative PPAR␥ or GW-9662. Inhibition of NF-B was also ineffective against rosiglitazone but abolished the stimulating effect of IL-1␤ on IL-1Ra. All PPAR isotypes were expressed constitutively in rat synoviocytes, but PPAR␥ decreased dramatically upon IL-1␤ exposure, whereas PPAR␤/␦ remained stable. Dominant-negative PPAR␤/␦ abolished the enhancement of IL-1Ra by rosiglitazone, whereas GW-501516 reproduced the effect of rosiglitazone on IL-1Ra secretion.Conclusion. Rosiglitazone stimulates IL-1Ra production by a PPAR␤/␦ mechanism in activated rat synovial fibroblasts, further contributing to its potential antiarthritic properties and opening new perspectives for the modulation of inflammatory genes by specific PPAR agonists in articular cells.

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Section: Discussionmentioning

confidence: 99%

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Moulin¹,

Bianchi²,

Boyault³

et al. 2005

Arthritis & Rheumatism

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“…Supporting this concept is the existence of a splice variant of the IL-1RAcP, which lacks a transmembrane anchor (28)(29)(30). This sIL-1RAcP is synthesized and released by the liver in somewhat the same way IL-1Ra is released by the liver; as an acutephase protein (31). In the report by Smeets and colleagues, overexpression of sIL-1RAcP likely formed a complex of IL-1␤ with sIL-1RII in the extracellular space ( Figure 2C), with the cell surface IL-1RII ( Figure 2D), or possibly with IL-1RI ( Figure 2D).…”

Section: What Accounts For the Differences Between Overexpression Of mentioning

confidence: 99%

The many worlds of reducing interleukin‐1

Dinarello¹

2005

Arthritis & Rheumatism

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“…The mRNA for icIL-1Ra2 was detected in activated fibroblasts, monocytes, neutrophils, and keratinocytes [21]. Finally, icIL-1Ra3 was detected by western blot analysis in cell lysates of LPS-stimulated neutrophils, monocytes, and hepatocytes, and corresponds to an alternative translation initiation product from sIL-1Ra mRNA [22,23].Our previous reports demonstrated that human and mouse primary hepatocytes are able to produce high levels of IL-1Ra in response to inflammatory challenge in vitro [22,24]. Hepatocytes might thus represent an important source of IL-1Ra during liver injury, although this hypothesis has not been formally examined.…”

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confidence: 98%

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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Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein.

Cited by 285 publications

References 60 publications

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

The many worlds of reducing interleukin‐1

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

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