IL-18 enhances collagen-induced arthritis by recruiting neutrophils via TNF-alpha and leukotriene B4 (original) (raw)
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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.
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.
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...
Combined Effects of IL-12 and IL-18 on the Induction of Collagen-Induced Arthritis
The Journal of Immunology, 2000
IL-18 expression has recently been detected in rheumatoid arthritis (RA) synovial membrane. We investigated the mechanisms by which IL-18-induced collagen-induced arthritis in DBA/1 mice primed intradermally with type II bovine collagen in IFA and boosted i.p. 21 days later with CII in saline. Mice were injected i.p. with rIL-12, rIL-18, or both (100 ng) during days ؊1 to 4 and again on days 20 -24. Control mice received PBS. Mice treated with IL-12 or IL-18 alone developed significantly higher incidence and more severe disease compared with controls. These were elevated further by combination treatment with IL-12 and IL-18. The cytokine treatments led to markedly enhanced synovial hyperplasia, cellular infiltration, and cartilage erosion compared with controls. Cytokine-treated mice produced significantly more IFN-␥, TNF-␣, and IL-6 than the controls. Interestingly, IL-18treated mice produced more TNF-␣ and IL-6, but less IFN-␥, compared with mice treated with IL-12. Furthermore, splenic macrophages from DBA/1 mice cultured in vitro with IL-18, but not IL-12, produced substantial amounts of TNF-␣. Mice treated with IL-18 or IL-18 plus IL-12 produced markedly more IgG1 and IgG2a anti-collagen Ab compared with controls, whereas IL-12 treatment only led to an enhanced IgG2a response. Together these results demonstrate that IL-18 can promote collagen-induced inflammatory arthritis through mechanisms that may be distinct from those induced by IL-12.
A Role for IL-18 in Neutrophil Activation
The Journal of Immunology, 2001
IL-18 expression and functional activity has been identified in several autoimmune and infectious diseases. To clarify the potential role of IL-18 during early innate immune responses, we have explored the capacity of IL-18 to activate neutrophils. Human peripheral blood-derived neutrophils constitutively expressed IL-18R (␣ and ) commensurate with the capacity to rapidly respond to IL-18. IL-18 induced cytokine and chemokine release from neutrophils that was protein synthesis dependent, upregulated CD11b expression, induced granule release, and enhanced the respiratory burst following exposure to fMLP, but had no effect upon the rate of neutrophil apoptosis. The capacity to release cytokine and chemokine was significantly enhanced in neutrophils derived from rheumatoid arthritis synovial fluid, indicating differential responsiveness to IL-18 dependent upon prior neutrophil activation in vivo. Finally, IL-18 administration promoted neutrophil accumulation in vivo, whereas IL-18 neutralization suppressed the severity of footpad inflammation following carrageenan injection. The latter was accompanied by reduction in tissue myeloperoxidase expression and suppressed local TNF-␣ production. Together, these data define a novel role for IL-18 in activating neutrophils and thereby promoting early innate immune responses.
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.
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).