A proinflammatory role for IL-18 in rheumatoid arthritis

Gracie, J. Alastair; Forsey, Rosalyn; Chan, Weng Onn; Gilmour, Ashley; Leung, Bernard P.; Greer, Morag R.; Kennedy, Kristy; Robert, Caroline; Wei, Xiaoguang; Xu, Damo; Field, Max; Foulis, Alan K.; Liew, Foo Y.; McInnes, Iain B.

doi:10.1172/jci7317

Cited by 586 publications

(556 citation statements)

References 44 publications

Supporting

Mentioning

523

Contrasting

Unclassified

Order By: Relevance

“…The observed proinflammatory profile of IL-18 was first described in studies by Gracie et al 18 and Wei et al, 21 in which they demonstrated the pivotal role of IL-18 in the development of inflammatory arthritis. Other studies by Joosten et al 22,23 verified the importance of IL-18 in experimental arthritis through systemic neutralization of IL-18.…”

Section: Discussionmentioning

confidence: 75%

“…Besides this systemic role of IL-18, it has been demonstrated that IL-18 is also produced in high amounts by the synovial lining of RA patients. 16,18 As a result of these high levels of IL-18 in local inflammatory processes intra-articular neutralization of IL-18 by adenoviral overexpressed IL-18BPc during onset of CIA could be effective. While control-treated mice developed a progressive inflammatory articular disease, Exogenous IL-18BPc ameliorates CIA RL Smeets et al intra-articular overexpression of IL-18BPc before clinical manifestation of the CIA resulted in amelioration of the arthritis.…”

Section: Discussionmentioning

confidence: 99%

“…6 IL-18 is highly expressed in RA synovium and correlates with inflammation. 16 Significantly elevated concentrations are found in both serum 17 and synovial fluid of RA patients, 18,19 and can be rapidly reduced by anti-TNFa treatment. 20 Furthermore, the influential role of IL-18 in experimental arthritis was obtained from studies with IL-18 À/À mice, which showed impaired development of collagen-induced arthritis (CIA).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Adenoviral delivery of IL-18 binding protein C ameliorates Collagen-Induced Arthritis in mice

Smeets¹,

Loo²,

Arntz³

et al. 2003

Gene Ther

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Adenoviral delivery of IL-18 binding protein C ameliorates Collagen-Induced Arthritis in mice

Smeets¹,

Loo²,

Arntz³

et al. 2003

Gene Ther

View full text Add to dashboard Cite

“…Negating the function of endogenous IL-18 with neutralizing IL-18 antibodies has also been effective in mouse models of hepatitis and Guillain Barrè syndrome [12,13]. Conversely, exogenously administered IL-18 exacerbates the course of type II collagen-induced arthritis and systemic lupus erythematosus-like syndrome in mice [14,15].…”

Section: Discussionmentioning

confidence: 99%

Essential pathogenic role of endogenous IL‐18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL‐18‐binding protein: Fc construct

Nicoletti¹,

Marco²,

Papaccio³

et al. 2003

Eur J Immunol

View full text Add to dashboard Cite

IL-18 is a cytokine structurally and functionally related to IL-1 that, in synergy with IL-12, stimulates the synthesis of IFN-+ from T lymphocytes and natural killer cells. Because IFN-+ plays a key pathogenic role in the development of murine immunoinflammatory diabetes induced by multiple low doses of streptozotocin (STZ) we investigated the effect of negating the actions of endogenous IL-18 in this model by administering recombinant IL-18-binding protein:Fc (IL-18 bp:Fc). C57BL/6 mice were injected once daily with 40 mg/kg STZ for 5 consecutive days, day 0 being the first day of STZ challenge. Relative to control animals treated in parallel with either PBS or human IgG, mice treated from day -3 to day 7 with daily doses of 150 ? g of IL-18 bp:Fc exhibited lower incidence of diabetes and milder insulitis. In contrast, mice that were treated with IL-18 bp:Fc from day 7 to day 14 exhibited clinical and histological signs of STZ-induced diabetes similar to those of control mice treated with IgG. The protective effect of IL-18 bp:Fc was accompanied by modified ex vivo immune responses, in that spleen cells and peritoneal macrophages contained fewer IFN-+ secreting cells and released lower amounts of nitrite (an index of nitric oxide production) and IL-1 g . We conclude that intact IL-18 function is essential for the full diabetogenic effect of low dose STZ in C57BL/6 mice.

show abstract

“…12,22,23 Although some investigators have reported that RA patients have high concentrations of serum IL-18, 22 it is commonly accepted that IL-18 concentrations are higher in synovial fluid than in serum. 12 IL-18 would exert pathological effects only within affected synovium in RA, while systemic and abundant production of IL-18 would be specific for AOSD. These phenomena are consistent with the present data showing that a certain diplotype configuration is frequently observed only in AOSD.…”

Section: Il-18 Gene Polymorphisms In Aosd T Sugiura Et Almentioning

confidence: 99%

Association between adult-onset Still's disease and interleukin-18 gene polymorphisms

et al. 2002

View full text Add to dashboard Cite

Recently, we reported that serum concentration of IL-18 is strikingly high in patients with adult-onset Still's disease (AOSD). The aim of the present study was to screen for genetic polymorphisms in the human IL-18 (hIL-18) gene and to determine the association of polymorphisms with susceptibility to AOSD. We investigated the 6.7 kb region upstream of exon 2 of hIL-18 gene, in which a promoter activity had been reported. Sixteen AOSD patients, 144 rheumatoid arthritis (RA) patients and 92 healthy control individuals were studied. We found seven single nucleotide polymorphisms and a single 9 bp insertion which were frequently present in the AOSD patients. Three haplotypes including a unique combination of these polymorphisms were also determined. Of them, haplotype S01 contained all eight of these polymorphisms. The frequency of individuals carrying a diplotype configuration, ie a combination of two haplotypes, of S01/S01 was significantly higher in the AOSD patients than in the healthy controls (P ¼ 0.00059, Fischer's exact probability test, odds ratio [OR] ¼ 7.81, 95% confidence interval [95% CI] ¼ 2. 48-24.65) and the RA patients (P ¼ 0.015, Fischer's exact probability test, OR ¼ 4.0, 95% CI ¼ 1.39-11.54). We therefore conclude that possession of the diplotype configuration of S01/S01 is a major genetic risk factor for susceptibility to AOSD.

show abstract

A proinflammatory role for IL-18 in rheumatoid arthritis

Abstract: Figure 1(a) IL-18 mRNA was detected in RA and OA synovial membranes by RT-PCR (representative of 20 RA and 10 OA tissues). (b) Significantly higher levels of IL-18 were detected in RA SF than in sera (18 matched samples assayed after removal of rheumatoid factor).

Cited by 586 publications

References 44 publications

Adenoviral delivery of IL-18 binding protein C ameliorates Collagen-Induced Arthritis in mice

Adenoviral delivery of IL-18 binding protein C ameliorates Collagen-Induced Arthritis in mice

Essential pathogenic role of endogenous IL‐18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL‐18‐binding protein: Fc construct

Association between adult-onset Still's disease and interleukin-18 gene polymorphisms

Contact Info

Product

Resources

About