Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis (original) (raw)
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Cells, 2019
Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18Rα KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration...
Annals of the Rheumatic Diseases, 2004
To measure synovial tissue interleukin-18 (IL-18) expression in patients with inflammatory arthritis, and to identify associations with serum levels, disease activity, and response to treatment. Methods: Synovial tissue biopsies and serum samples were obtained from patients with early, active, rheumatoid arthritis (RA) (n = 12), undifferentiated seronegative arthritis (SnA) (n = 9), psoriatic arthritis (PsA) (n = 5), and reactive arthritis (ReA) (n = 2) before and one year after introduction of disease modifying antirheumatic drug (DMARD) treatment. Osteoarthritis (OA) tissues were compared. Tissue IL-18 expression was determined after immunohistochemical staining using a semiquantitative scale. Serum IL-18 was measured by enzyme linked immunosorbent assay. Results: Before treatment was started, tissue IL-18 expression was increased in each diagnostic group compared with OA (p,0.05). Tissue IL-18 expression was correlated with serum C reactive protein levels (r = 0.53, p = 0.003) but not with serum IL-18. After DMARD treatment, 12 patients (five RA, four SnA, three PsA) were re-evaluated. Decreases in tissue IL-18 expression were observed in eight, although the trend did not reach significance (p = 0.068). Changes in tissue IL-18 expression were correlated with changes in serum IL-18 (r = 0.62, p = 0.041) and C reactive protein (r = 0.72, p = 0.009). Conclusions: Synovial tissue IL-18 expression was correlated with disease activity in inflammatory arthritis. After treatment, tissue levels changed in parallel with changes in serum IL-18 and with changes in the acute phase response. These observations support a role for IL-18 in the pathophysiology of inflammatory arthritis.
IL-18 Enhances Collagen-Induced Arthritis by Recruiting Neutrophils Via TNF- and Leukotriene B4
The Journal of Immunology, 2003
IL-18 expression and functional activity have been associated with a range of autoimmune diseases. However, the precise mechanism by which IL-18 induces such pathology remains unclear. In this study we provide direct evidence that IL-18 activates neutrophils via TNF-␣ induction, which drives the production of leukotriene B 4 (LTB 4 ), which in turn leads to neutrophil accumulation and subsequent local inflammation. rIL-18 administered i.p. resulted in the local synthesis of LTB 4 and a rapid influx of neutrophils into the peritoneal cavity, which could be effectively blocked by the LTB 4 synthesis inhibitor MK-886 (MK) or its receptor antagonist CP-105,696. IL-18-induced neutrophils recruitment and LTB 4 production could also be blocked by a neutralizing anti-TNF-␣ Ab. In addition, IL-18 failed to induce neutrophil accumulation in vivo in TNFRp55 ؊/؊ mice. In an IL-18-dependent murine collagen-induced arthritis model, administration of MK significantly inhibited disease severity and reduced articular inflammation and joint destruction. Furthermore, MK-886-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Finally, we showed that IL-18-activated human peripheral blood neutrophils produced significant amounts of LTB 4 that were effectively blocked by the MK. Together, these findings provide a novel mechanism whereby IL-18 can promote inflammatory diseases. Abbreviations used in this paper: ICE, IL-1-converting enzyme; LTB 4 , leukotriene B 4 ; CIA, collagen-induced arthritis; RA, rheumatoid arthritis; rm, recombinant murine; PB, peripheral blood; i.d., intradermal; CII, acidified bovine type II collagen; MK, LTB 4 synthesis inhibitor MK-886; CP, LTB 4 receptor antagonist CP-105,696.
Interleukin-18: a therapeutic target in rheumatoid arthritis?
Arthritis research & therapy, 2005
Interleukin 18 (IL-18), a member of the IL-1 superfamily of cytokines has been demonstrated to be an important mediator of both innate and adaptive immune responses. Several reports have implicated its role in the pathogenesis of rheumatoid arthritis (RA). Although biologic therapy is firmly established in the treatment of a number of inflammatory diseases including RA, partial and non-responder patients constitute residual unmet clinical need. The aim of this article is to briefly review the biology of, and experimental approaches to IL-18 neutralisation, together with speculation as to the relative merits of IL-18 as an alternative to existing targets.
IL-18 enhances collagen-induced arthritis by recruiting neutrophils via TNF-alpha and leukotriene B4
Journal of immunology (Baltimore, Md. : 1950), 2003
IL-18 expression and functional activity have been associated with a range of autoimmune diseases. However, the precise mechanism by which IL-18 induces such pathology remains unclear. In this study we provide direct evidence that IL-18 activates neutrophils via TNF-alpha induction, which drives the production of leukotriene B(4) (LTB(4)), which in turn leads to neutrophil accumulation and subsequent local inflammation. rIL-18 administered i.p. resulted in the local synthesis of LTB(4) and a rapid influx of neutrophils into the peritoneal cavity, which could be effectively blocked by the LTB(4) synthesis inhibitor MK-886 (MK) or its receptor antagonist CP-105,696. IL-18-induced neutrophils recruitment and LTB(4) production could also be blocked by a neutralizing anti-TNF-alpha Ab. In addition, IL-18 failed to induce neutrophil accumulation in vivo in TNFRp55(-/-) mice. In an IL-18-dependent murine collagen-induced arthritis model, administration of MK significantly inhibited disease...
Arthritis & Rheumatism, 2003
Objective. To examine the expression patterns of interkeukin-18 (IL-18) in synovial biopsy tissue of patients with rheumatoid arthritis (RA), and to determine whether expression of this primary cytokine is related to the expression of other cytokines and adhesion molecules and related to the degree of joint inflammation. Methods. Biopsy specimens of knee synovial tissue either without synovitis (n ؍ 6) or with moderate or severe synovitis (n ؍ 11 and n ؍ 12, respectively) were obtained from 29 patients with active RA. Paraffinembedded, snap-frozen sections were used for immunohistochemical detection of IL-18, tumor necrosis factor ␣ (TNF␣), IL-1, IL-12, and IL-17. Furthermore, adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin, and cell markers CD3, CD14, and CD68 were stained. Results. IL-18 staining was detectable in 80% of the RA patients, in both the lining and sublining of the knee synovial tissue. IL-18 expression in the synovial tissue was strongly correlated with the expression of IL-1
Mechanisms of Inhibition of Collagen-Induced Arthritis by Murine IL-18 Binding Protein
The Journal of Immunology, 2003
IL-18 is an important cytokine in autoimmune and inflammatory diseases through the induction of IFN-␥, TNF-␣, and IL-1. We report herein that collagen-induced arthritis (CIA) in mice is inhibited by treatment with murine IL-18 binding protein (mIL-18BP). CIA was induced in DBA/1J mice by the injection of bovine type II collagen (CII) in IFA with added Mycobacterium tuberculosis on days 0 and 21. The mice were then treated for 3 wk with PBS or with two doses of mIL-18BP (0.5 and 3 mg/kg) as a fusion protein with the Fc portion of murine IgG1. Both the clinical disease activity scores and the histological scores of joint damage were reduced 50% in mice treated with either dose of mIL-18BP. Proliferation of CII-stimulated spleen and lymph node cells as well as the change in serum levels of IgG1 and IgG2a Ab to collagen between days 21 and 42 were decreased in mice treated with mIL-18BP. The production of IFN-␥, TNF-␣, and IL-1 in cultured spleen cells was reduced by in vivo treatment with low dose, but not high dose, mIL-18BP. FACS analysis showed a slight decrease in NK cells and an increase in CD4 ؉ T cells in spleens of mice treated with mIL-18BP. The steady state mRNA levels of IFN-␥, TNF-␣, and IL-1 in isolated joints were all decreased in mice treated with both doses of mIL-18BP. The mechanisms of mIL-18BP inhibition of CIA include reductions in cell-mediated and humoral immunity to collagen as well as decreases in production of proinflammatory cytokines in the spleen and joints.
A proinflammatory role for IL18 in rheumatoid arthritis
Journal of Clinical Investigation, 1999
(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).