TNF-α is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist–deficient mice

Horai, Reiko; Nakajima, Ayako; Habiro, Katsuyoshi; Kotani, Masahiro; Nakae, Susumu; Matsuki, Taizo; Nambu, Aya; Saijo, Shinobu; Kotaki, Hayato; Sudo, Katsuko; Okahara, Akihiko; Tanioka, Hidetoshi; Ikuse, Toshimi; Ishii, Naoto; Schwartzberg, Pamela L.; Ryo, Akihide; Iwakura, Yoichiro

doi:10.1172/jci20742

Cited by 114 publications

(96 citation statements)

References 28 publications

(14 reference statements)

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“…Arthritis in these mice arises from disturbed immune homeostasis due to excessive IL-1 signaling, which results in the induction of costimulatory molecules such as OX40 and CD40 ligand on T cells, thereby enhancing APC-T cell interaction and mediating T cell autoimmunity (26,27). For therapeutic treatment of IL-1Ra Ϫ/Ϫ mice, we chose a lower dose but a longer treatment course than that for existing CIA because of the milder joint destruction and the more chronic progress of arthritis in this model.…”

Section: Discussionmentioning

confidence: 99%

“…The protective effects of the TLR-4 antagonist in CIA were not mediated by a disruption of the adaptive immune response disturbing the development of autoimmunity in this model. In addition, treatment with the TLR-4 antagonist reduced the clinical and histopathologic features of arthritis in IL-1Ra Ϫ/Ϫ mice, in which an autoimmune T cell-mediated arthritis develops spontaneously due to unbalanced IL-1 signaling (26,27).…”

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confidence: 99%

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Inhibition of toll‐like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis

Abdollahi‐Roodsaz

Joosten

Roelofs

et al. 2007

Arthritis & Rheumatism

282

219

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Objective. Degeneration of extracellular matrix of cartilage leads to the production of molecules capable of activating the immune system via Toll-like receptor 4 (TLR-4). The objective of this study was to investigate the involvement of TLR-4 activation in the development and progression of autoimmune destructive arthritis.Methods. A naturally occurring TLR-4 antagonist, highly purified lipopolysaccharide (LPS) from Bartonella quintana, was first characterized using mouse macrophages and human dendritic cells (DCs). Mice with collagen-induced arthritis (CIA) and mice with spontaneous arthritis caused by interleukin-1 receptor antagonist (IL-1Ra) gene deficiency were treated with TLR-4 antagonist. The clinical score for joint inflammation, histologic characteristics of arthritis, and local expression of IL-1 in joints were evaluated after treatment.Results. The TLR-4 antagonist inhibited DC maturation induced by Escherichia coli LPS and cytokine production induced by both exogenous and endogenous TLR-4 ligands, while having no effect on these parameters by itself. Treatment of CIA using TLR-4 antagonist substantially suppressed both clinical and histologic characteristics of arthritis without influencing the adaptive anti-type II collagen immunity crucial for this model. Treatment with TLR-4 antagonist strongly reduced IL-1␤ expression in articular chondrocytes and synovial tissue. Furthermore, such treatment inhibited IL-1-mediated autoimmune arthritis in IL-1Ra ؊/؊ mice and protected the mice against cartilage and bone pathology.Conclusion. In the present study, we demonstrate for the first time that inhibition of TLR-4 suppresses the severity of experimental arthritis and results in lower IL-1 expression in arthritic joints. Our data suggest that TLR-4 might be a novel target in the treatment of rheumatoid arthritis.Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology associated with chronic inflammation of peripheral joints. Today it is generally accepted that proinflammatory cytokines play an important role in the pathogenesis of RA (1); however, the mechanisms of initiation and perpetuation of the inflammatory cascade in RA are still unknown.Toll-like receptors (TLRs) are a family of pattern recognition receptors that are involved in the recognition of conserved pathogen-associated molecular patterns (2). Ligand binding to TLRs initiates a signaling cascade that leads to the activation of the NF-B and interferon regulatory factor 3 transcription factors and MAPKs, which in turn promote the production of inflammatory cytokines, chemokines, and tissuedestructive enzymes and the expression of costimulatory molecules on antigen-presenting cells (APCs). These costimulatory molecules provide a second signal to T cells to initiate the adaptive immune response (3,4

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of toll‐like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis

Abdollahi‐Roodsaz

Joosten

Roelofs

et al. 2007

Arthritis & Rheumatism

282

219

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“…Excess IL-1␤ signal induced the increased production of IL-23 in IL-1Ra Ϫ/Ϫ mice compared with its effects in WT mice. Iwakura and colleagues (22)(23)(24) have reported that IL-1Ra Ϫ/Ϫ mice that are also deficient in IL-17 or TNF-␣ do not develop spontaneous arthritis. Interestingly, they found that IL-1 does not directly induce the production of IL-17 or TNF-␣ by CD4 ϩ T cells.…”

Section: Discussionmentioning

confidence: 99%

“…High levels of autoantibodies directed against Ig, type II collagen, and dsDNA are detectable in serum (22). In this model, excess IL-1 signaling due to a deficiency in the IL-1Ra causes T cell-mediated autoimmunity, resulting in joint-specific inflammation and bone destruction (22)(23)(24). IL-17 expression is greatly enhanced in IL-1Ra Ϫ/Ϫ mice, suggesting that IL-17 activity is involved in the pathogenesis of arthritis in these mice.…”

Section: Stat3 and Nf-b Signal Pathway Is Required For Il-23-mediatedmentioning

confidence: 95%

STAT3 and NF-κB Signal Pathway Is Required for IL-23-Mediated IL-17 Production in Spontaneous Arthritis Animal Model IL-1 Receptor Antagonist-Deficient Mice

Cho

Kang

Moon

et al. 2006

The Journal of Immunology

287

196

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IL-23 is a heterodimeric cytokine composed of a p19 subunit and the p40 subunit of IL-12. IL-23 has proinflammatory activity, inducing IL-17 secretion from activated CD4+ T cells and stimulating the proliferation of memory CD4+ T cells. We investigated the pathogenic role of IL-23 in CD4+ T cells in mice lacking the IL-1R antagonist (IL-1Ra−/−), an animal model of spontaneous arthritis. IL-23 was strongly expressed in the inflamed joints of IL-1Ra−/− mice. Recombinant adenovirus expressing mouse IL-23 (rAd/mIL-23) significantly accelerated this joint inflammation and joint destruction. IL-1β further increased the production of IL-23, which induced IL-17 production and OX40 expression in splenic CD4+ T cells of IL-1Ra−/− mice. Blocking IL-23 with anti-p19 Ab abolished the IL-17 production induced by IL-1 in splenocyte cultures. The process of IL-23-induced IL-17 production in CD4+ T cells was mediated via the activation of Jak2, PI3K/Akt, STAT3, and NF-κB, whereas p38 MAPK and AP-1 did not participate in the process. Our data suggest that IL-23 is a link between IL-1 and IL-17. IL-23 seems to be a central proinflammatory cytokine in the pathogenesis of this IL-1Ra−/− model of spontaneous arthritis. Its intracellular signaling pathway could be useful therapeutic targets in the treatment of autoimmune arthritis.

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“…It is rare for IL-1ra -/-mice to develop arthritis in all four paws, thus the arthritis score seldom reaches the maximum. T and B cells are important for the spontaneous development of arthritis in IL-1ra -/-mice and the involvement of OX-40 and CD40L is suggested [18]. IL-17 production from T cells has been shown to play a crucial role in the spontaneous development of arthritis in IL-1ra -/-mice [19].…”

Section: Introductionmentioning

confidence: 99%

Anti‐type II collagen antibody accelerates arthritis via CXCR2‐expressing cells in IL‐1 receptor antagonist‐deficient mice

et al. 2007

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Arthritis can be induced in mice by the injection of anti-type II collagen (anti-CII) Ab and LPS. To elucidate the role of IL-1 receptor antagonist (IL-1ra) in Ab-induced arthritis, WT and IL-1ra -/-mice were administered anti-CII Ab and LPS. These IL-1ra-/-mice developed severe arthritis even at low doses of anti-CII Ab and LPS, while WT mice did not. The cells that invaded the arthritic joints were mainly Gr-1 + neutrophils, and the number of the cells in the joints remained high over 4 weeks in the IL-1ra -/-mice. KC, a ligand for CXCR2, is found in higher levels in the arthritic paws of IL-1ra -/-mice compared with the WT, and most of the cells that infiltrated into the joints of the IL-1ra -/-mice were CXCR2-expressing neutrophils. Administration of anti-CXCR2 Ab completely inhibited arthritis development. The anti-CXCR2 Ab decreased the number of neutrophils in the blood and also inhibited the migration of neutrophils to KC. These results suggested that the high susceptibility of IL-1ra -/-mice to anti-CII Ab-induced arthritis was due to the higher expression of chemotactic factors like KC and the sustained infiltration of CXCR2-expressing neutrophils into the joints.

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TNF-α is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist–deficient mice

Cited by 114 publications

References 28 publications

Inhibition of toll‐like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis

Inhibition of toll‐like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis

STAT3 and NF-κB Signal Pathway Is Required for IL-23-Mediated IL-17 Production in Spontaneous Arthritis Animal Model IL-1 Receptor Antagonist-Deficient Mice

Anti‐type II collagen antibody accelerates arthritis via CXCR2‐expressing cells in IL‐1 receptor antagonist‐deficient mice

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