IL-1 mediates TNF-induced osteoclastogenesis

Shi, Wei; Kitaura, Hideki; Zhou, Ping; Ross, F. Patrick; Teitelbaum, Steven L.

doi:10.1172/jci200523394

Cited by 611 publications

(386 citation statements)

References 25 publications

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“…IL-1␤ is considered to play an especially critical role downstream of TNF␣, based on a report that TNF-induced RANKL synthesis by bone marrow stromal cells was abolished by IL-1 receptor antagonist (IL-1Ra) and was absent in stromal cells derived from type I IL-1R-deficient mice (33). The present study showed that APRIL stimulated RA FLS to produce both TNF␣ and IL-1␤.…”

supporting

confidence: 52%

Rheumatoid arthritis fibroblast‐like synoviocytes express BCMA and are stimulated by APRIL

Nagatani¹,

Itoh²,

Nakajima³

et al. 2007

Arthritis & Rheumatism

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Objective. Fibroblast-like synoviocytes (FLS) are among the principal effector cells in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to examine the variety of stimulating effects of APRIL and its specific effect on FLS in the affected RA synovium.Methods. Synovium and serum samples were obtained from patients with RA, patients with osteoarthritis (OA), and healthy subjects. Soluble APRIL proteins were assayed by enzyme-linked immunosorbent assay. The relative gene expression of APRIL, BCMA, interleukin-6 (IL-6), tumor necrosis factor ␣ (TNF␣), IL-1␤, and RANKL was assessed in RA and OA FLS by polymerase chain reaction. Effects of APRIL on the production of proinflammatory cytokines and RANKL in RA FLS were investigated by flow cytometry and with the use of a BCMA-Fc fusion protein.

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supporting

confidence: 52%

Rheumatoid arthritis fibroblast‐like synoviocytes express BCMA and are stimulated by APRIL

Nagatani¹,

Itoh²,

Nakajima³

et al. 2007

Arthritis & Rheumatism

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“…TNF-a also induces the expression of IL-1, which has been identified as an important mediator for osteoclast formation. In particular, IL-1 stimulates RANKL expression as well as RANK expression rendering monocytes more susceptible to osteoclastogenesis [6,16]. Aside IL-1, T-cell-derived lymphokines have been elegantly documented to be instrumental in regulating osteoclast differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, aside from IL-4 and IL-12, up-regulation of Foxp3 expression following IL-17A inhibition may also contribute to the bone sparing effect of IL-17A blockade. Treg cells are not only considered to balance the effects of inflammatory T-cell lineages such as Th17 cells but they also suppress osteoclast formation via cell-cell contact-dependent mechanisms involving CTLA-4 [16].…”

Section: Discussionmentioning

confidence: 99%

“…IL-12 inhibition did yield very similar effects, albeit rescue of bone protection did not achieve (Fig. 5B), suggesting that upregulation of anti-osteoclastogenic IL-4 and IL-12 are of key importance in mediating the bone protective effect of IL-17 neutralization.Blockade of IL-17A in the absence of IL-1 abrogates TNF-mediated arthritis and bone destructionAs IL-1 is an important downstream mediator of TNF-induced bone destruction [6,16] and is also involved in the differentiation of Th17 cells [17], we were interested to test the influence of IL-1, when blocking IL-17A in TNF-a-mediated arthritis. We therefore blocked IL-17 in IL-1 À/À hTNFtg mice, which developed inflammatory arthritis but showed less bone destruction.…”

mentioning

confidence: 99%

“…As IL-1 is an important downstream mediator of TNF-induced bone destruction [6,16] and is also involved in the differentiation of Th17 cells [17], we were interested to test the influence of IL-1, when blocking IL-17A in TNF-a-mediated arthritis. We therefore blocked IL-17 in IL-1 À/À hTNFtg mice, which developed inflammatory arthritis but showed less bone destruction.…”

mentioning

confidence: 99%

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Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

et al. 2011

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Tumour necrosis factor alpha (TNF-a) is a major inducer for inflammation and bone loss. Here, we investigated whether interleukin (IL)-17 plays a role in TNF-a-mediated inflammation and bone resorption. Human TNF-a transgenic (hTNFtg) mice were treated with a neutralizing anti-IL-17A antibody and assessed for inflammation, cartilage and bone damage. T-cell transcription factors and lymphokine patterns were measured in the LNs. IL-17A inhibition in the absence of IL-1 was also evaluated by treating hTNFtg/IL-1 À/À mice with an IL-17A neutralizing antibody. IL-17A neutralization had only minor effects on TNF-a-induced inflammation but effectively reduced local and systemic bone loss by blocking osteoclast differentiation in vivo. Effects were based on a shift to bone-protective T-cell responses such as enhanced Th2 differentiation, IL-4 and IL-12 expression and Treg cell numbers. Whereas inflammation in hTNFtg/IL-1 À/À mice was highly sensitive to IL-17A blockade, no shift in the T-cell lineages and no additional benefit on bone mass were observed in response to IL-17A neutralization. We thus conclude that IL-17A is a key mediator of TNF-a-induced bone loss by closely interacting with IL-1 in blocking bone protective T-cell responses.Key words: Arthritis . Cytokine . IL-17 . Osteoclast . T cells IntroductionBone is continuously remodelled in life by the interaction between bone resorbing cells, termed osteoclasts, with boneforming cells, termed osteoblasts [1]. Bone resorption and bone formation are usually in physiological balance, maintaining a stable bone mass. An imbalance between bone resorption and bone formation leads to bone loss and several factors such as age, oestrogen deficiency or drug therapy alter this fine balance between osteoclasts and osteoblasts in favour of the former. Immune activation and inflammation is one the pivotal condi-Ã These authors contributed equally to this work. 413tions perturbing this fine balance of bone remodelling ultimately leading to enhanced bone loss [2]. Autoimmune inflammatory diseases, such as chronic arthritis are characterized by activation of the innate and adaptive immune system eliciting profound local and systemic bone loss. Progressive destruction of the joints is associated with pain, functional impairment and low quality of life. In addition, loss of systemic bone mass causes osteoporosis and increased fracture risk in patients with inflammatory arthritis [3]. This tight link between inflammation and bone loss is mediated by inducible expression of factors, such as M-CSF and RANKL, which are essential for osteoclast differentiation [4]. In addition, inflammatory cytokines produced by monocytes and resident mesenchymal cells are of key importance for osteoclast formation, as they regulate expression of RANKL and also sensitize monocytes for osteoclast differentiation. In this context, TNF-a, and IL-1 are of particular key importance for osteoclast formation and bone resorption in inflammatory tissue [5,6].Aside from classical pro-inflammatory mediators like ...

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Anti‐Inflammatory/Analgesics: An In‐Depth Look atp38MAPKinases

Brown

2011

Pharmaceutical Sciences Encyclopedia

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Inflammation is a complex process controlled by numerous positive and negative regulators. The p38 MAP kinase pathway is integral to the production of mediators that drive inflammation and pain and the cellular responses to these mediators. If not properly controlled, it can cause dire effects in the inflammatory, immune, and nervous systems that manifest in the development of chronic pain and inflammatory disease. As this chapter will discuss, newer versions of these molecular inhibitors must be designed in a manner that is more mindful of the complexity of p38 and the inflammatory response to reach their potential as an effective anti‐inflammatory and analgesic therapy.

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IL-1 mediates TNF-induced osteoclastogenesis

Cited by 611 publications

References 25 publications

Rheumatoid arthritis fibroblast‐like synoviocytes express BCMA and are stimulated by APRIL

Rheumatoid arthritis fibroblast‐like synoviocytes express BCMA and are stimulated by APRIL

Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

Anti‐Inflammatory/Analgesics: An In‐Depth Look atp38MAPKinases

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