Role Of Interleukin-1 Receptor Antagonist Research Articles

Deficiency of interleukin-1 receptor antagonist promotes neointimal formation after injury.

The cytokine interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Activity of this cytokine is modulated endogenously via the IL-1 receptor antagonist (IL-1Ra). The role of IL-1Ra in neointima formation after injury, however, is poorly understood. Using IL-1Ra-deficient (IL-1Ra-/-; backcrossed 8 generations into the C57BL/6J background) and wild-type (IL-1Ra+/+) mice, we investigated neointimal formation 3 weeks after femoral artery injury induced by an external vascular cuff model. Intima and media thicknesses were measured, and the intima/media ratio was calculated. The mean intimal thickness and the intima/media ratio of IL-1Ra-/- mice increased by 249% (31.8+/-2.9 microm [n=10] versus 9.1+/-0.7 microm [n=10]; P<0.0001) and 257% (2.5+/-0.2 versus 0.7+/-0.1; P<0.0001), respectively, compared with IL-1Ra+/+ mice. No significant differences were observed in the medial thickness. Control immunostaining for IL-1Ra in injured vessels localized IL-1beta and the endogenous inhibitor in the endothelium and inflammatory cells of the adventitia in IL-1Ra+/+ but not IL-1Ra-/- mice. The absence of IL-1Ra promotes neointimal formation in mice after injury. These results suggest that endogenous IL-1Ra may suppress other occlusive vascular responses to injury, such as atherosclerosis and restenosis after angioplasty.

The role of interleukin-1 receptor antagonist in the prevention and treatment of disease

The role of interleukin-1 receptor antagonist in the prevention and treatment of disease

Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, where family data support substantial heritability.(1) To date, association studies focussed mainly on genes regulating dopaminergic neurotransmission.(2)Interleukin-1 (IL-1) activity in the brain has been implicated with differentiation of dopaminergic neurons(3,4) and modulation of central monoaminergic reactivity.(5) We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) gene variable number tandem repeat (VNTR) polymorphism,(6) in a sample of 86 children with DSM-IV ADHD and their parents. Transmission disequilibrium analysis showed increased transmission of the IL-1Ra 4-repeat allele (chi(2) = 4.07, P = 0.04) and decreased transmission of the 2-repeat allele (chi(2) = 4.59, P = 0.03) to affected children. The 4-repeat allele was associated with a significantly increased risk for ADHD (chi(2) = 4.46, df 1, P = 0.035, RR = 1.292, 95% CI 1.01-1.66). The IL-1Ra 2-repeat allele was associated with a significantly decreased risk for ADHD (chi(2) = 4.65, df 1, P = 0.03, RR = 0.763, 95% CI 0.59-0.98). If replicated, this finding may point to a role for brain cytokine activity in the etiopathogenesis of ADHD.

Cell density regulates neutrophil IL-8 synthesis: role of IL-1 receptor antagonist and soluble TNF receptors.

Although cytokine synthesis in polymorphonuclear leukocytes (PMN) was shown to be modulated by soluble mediators, the impact of microenvironmental conditions has not been elucidated. In this study, we investigated the effect of cell density on cytokine release from human neutrophils. PMN were cultured at various cell densities (10 x 10(6) PMN/ml; 60 x 10(6) PMN/ml), and LPS-induced release of cytokines was quantified by ELISA technique. Upon an increase in PMN density, secretion of the CXC chemokine IL-8 was progressively reduced. This effect was paralleled by a decrease in IL-8 mRNA. In contrast, TNF-alpha and IL-1beta rose proportionally with increasing cell density. The inhibition of IL-8 secretion was reproduced by conditioned media of PMN at high cell density, but was not affected by blocking beta(2) integrin-dependent adhesion. When analyzing the supernatant of LPS-challenged neutrophils, large amounts of soluble TNFRs p55 and p75 (sTNFRI, sTNFRII), and IL-1R antagonist (IL-1RA), rising constantly with the cell density, were detected. Interestingly, combined blocking of the bioactivities of these mediators completely restored neutrophil IL-8 secretion at high cell densities, with the anti-IL-1RA Ab being the more potent agent. Moreover, combined application of exogenous IL-1RA and sTNFRs to 10 x 10(6) PMN/ml reproduced the suppression of IL-8 generation. We conclude that neutrophil IL-8 synthesis is autoregulated, being suppressed under conditions of high cell density. IL-1RA and sTNFRs, accumulating under these circumstances, seem to be centrally involved in this regulatory mechanism by interfering with the IL-1beta- and TNF-alpha-dependent IL-8 generation. This feedback mechanism may control further neutrophil recruitment and activation in a neutrophil-rich environment, thereby preventing tissue destruction.

Cytokine imbalance in the pathogenesis of rheumatoid arthritis: The role of interleukin-1 receptor antagonist

Objectives: To summarize the role of cytokine imbalance in the pathogenesis of rheumatoid arthritis. Methods: The literature on cytokines in rheumatoid arthritis from American and European medical journals was reviewed. Results: An important role of interleukin (IL)-1 and tumor necrosis factor (TNF)-α in the mediation of tissue damage in the rheumatoid joint has been well established over the past 10 years. The IL-1 family consists of 2 agonists, IL-1α and IL-1β, and a specific naturally occurring receptor antagonist, IL-1Ra. Both forms of IL-1 induce intracellular responses through binding to the type 1 IL-1 receptor (IL-1R) on target cells. IL-1Ra binds to IL-1R with an avidity equal to that of IL-1 but fails to stimulate the cells, thus functioning as an inhibitor of IL-1 binding. Endogenous production of IL-1Ra is an important anti-inflammatory mechanism both in animal models of disease and in human disease. In the rheumatoid synovium, an imbalance exists in this system, because the relative levels of production of IL-1Ra are not adequate to effectively block the proinflammatory effects of IL-1. Studies in different animal models of inflammatory arthritis indicate that a deficiency of IL-1Ra relative to IL-1 leads to more severe disease and even to the spontaneous development of arthritis as observed in IL-1Ra knockout mice. A restoration of the balance between IL-1Ra and IL-1 in human disease can theoretically be achieved through the administration of recombinant IL-1ra protein, gene therapy with the IL-1Ra complementary DNA, or stimulation of production of endogenous IL-1Ra. Conclusions: An imbalance between proinflammatory cytokines and cytokine antagonists or inhibitors may be one factor predisposing to initiation or perpetuation of rheumatoid synovitis. Semin Arthritis Rheum 30:1-6 (Suppl 2). Copyright © 2001 by W.B. Saunders Company

Physiologic role of interleukin-1 receptor antagonist

Recent studies have described the spontaneous development of arthritis or vasculitis in IL-1 receptor antagonist (IL-1Ra) knockout mice bred on specific and different genetic backgrounds. The levels of both secreted and intracellular isoforms of IL-1Ra produced in the rheumatoid joint or in the arterial wall may not be adequate to effectively inhibit the excess amounts of locally produced IL-1. Thus, an imbalance between IL-1 and IL-1Ra may predispose to local inflammatory disease in particular tissues in the presence of other as yet unknown genetically influenced factors.

The role of interleukin-1 receptor antagonist in the experimental gastric ulcer model: [formula omitted], G. Wakabayashi, M. Shimazu, A. Yoshida, K. Iwata, and M. Kitajima. Depts. of Surgery, Tokyo Adventist Hospital, Tokyo. Depts. of Surgery, Keio University, School of Medicine, Tokyo

The role of interleukin-1 receptor antagonist in the experimental gastric ulcer model: [formula omitted], G. Wakabayashi, M. Shimazu, A. Yoshida, K. Iwata, and M. Kitajima. Depts. of Surgery, Tokyo Adventist Hospital, Tokyo. Depts. of Surgery, Keio University, School of Medicine, Tokyo

Increased IL-1 receptor antagonist (IL-1ra) production and decreased IL-1 beta/IL-1ra ratio in mononuclear cells from rheumatoid arthritis patients.

In order to investigate the possible role of IL-1 receptor antagonist (IL-1ra) in patients with rheumatoid arthritis (RA), this study was undertaken to measure the amounts of IL-1ra and interleukin-1 beta (IL-1 beta) protein produced by mononuclear cells (MNC) and to investigate the relationship between production of these cytokines and clinical parameters. The MNC were cultured for 24 h and the supernatants were measured for IL-1ra and IL-1 beta by ELISA kits. MNC from peripheral blood (PB) and synovial fluid of RA patients produced significantly higher amounts of IL-1ra than normal PBMNC (P < 0.01 and P < 0.05, respectively). When the IL-1 beta/IL-1ra ratio was calculated, IL-1 beta/IL-1ra ratios of RA PBMNC were significantly lower than those of normal PBMNC (P < 0.001). The IL-1 beta/IL-1ra ratio of RA PBMNC was significantly higher in active RA patients than in RA patients in remission (P < 0.02). The amounts of IL-1ra produced by stimulated RA PBMNC positively correlated with the joint score (P < 0.05), serum CRP levels (P < 0.05) and the amounts of IL-1 beta produced (P < 0.01). The amounts of IL-1ra produced by unstimulated RA PBMNC did not correlate with any of the clinical parameters studied. Gold sodium thiomalate (GST), but not auranofin, increased IL-1ra production in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)