Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction

Sato, Kojiro; Suematsu, Ayako; Okamoto, Kazuo; Yamaguchi, Akira; Morishita, Yasuyuki; Kadono, Yuho; Tanaka, Sakae; Kodama, Tatsuhiko; Akira, Shizuo; Iwakura, Yoichiro; Daniel, J.; Takayanagi, Hiroshi

doi:10.1084/jem.20061775

Cited by 1,353 publications

(749 citation statements)

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“…GM-CSF and IL-4 from Th2 cells also inhibit osteoclastogenesis and induce type 2 macrophages (M2) that refrain inflammatory responses and promote tissue remodeling [1,38,39]. In contrast, IL-17 from Th17 cells facilitates osteoclastogenesis by promoting chronic inflammation in microenvironments [40]. Ultimately, the fate of monocytes/macrophages may be determined by the net effects of cytokines and various membranous proteins, including 4-1BB.…”

Section: Discussionmentioning

confidence: 99%

The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

et al. 2008

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The 4-1BB is a costimulatory molecule similar to the receptor activator of NF-jB ligand (RANKL), both of which are key factors for the differentiation of osteoclasts and are expressed mainly by activated T cells. The 4-1BB shares common signaling pathways with RANK, suggesting a potential role in osteoclastogenesis. In this study, the role of 4-1BB and 4-1BB ligand (4-1BBL) in osteoclastogenesis was investigated using 4-1BB -/-and 4-1BB +/+ mice. Osteoclast precursors normally express 4-1BB and 4-1BBL after exposure to RANKL, which was confirmed by semi-quantitative RT-PCR and flow cytometry. The 4-1BB -/-mice had a slightly increased bone mass accompanied by a reduced osteoclastogenic ability of 4-1BB -/-bone marrow-derived macrophages (BMM) ex vivo. In addition, 4-1BB -/-BMM demonstrated hypophosphorylation of JNK and p38 and decreased induction of c-Fos in response to RANKL stimulation. Retroviral transduction of wild-type as well as partiallength 4-1BB, which lacks TNF receptor-associated factor 2-binding sites for signaling, restored the osteoclastogenic ability of 4-1BB -/-BMM. Furthermore, both recombinant 4-1BB and 4-1BBL enhanced RANKL-induced osteoclastogenesis by 4-1BB +/+ BMM and the induction of c-Fos and NFATc1.Together, these results indicate that 4-1BBL and 4-1BB expressed on osteoclast precursors enhance RANKL-induced osteoclastogenesis via bi-directional signaling, findings that may delineate the complex nature of the 4-1BBL and 4-1BB interaction.

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Section: Discussionmentioning

confidence: 99%

The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

et al. 2008

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“…The notion that CD4+ Th1 cells are central to the cell-mediated immunity events associated with the disease, particularly through interferon-γ production, is now challenged by the discovery of the interleukin-17-producing Th17 population [10]. Although it has been proposed that Th17 cells confer specific osteoclast-inducing activity [11], their preceise role in periodontitis is still unclear. On the molecular level, the process of bone resorption is determined by the interplay of members of the tumor necrosis factor (TNF) ligand and receptor families [12].…”

Section: Introductionmentioning

confidence: 99%

Porphyromonas gingivalis Induces RANKL in T-cells

2010

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Porphyromonas gingivalis is an oral pathogen highly implicated in chronic periodontitis, a disease characterized by inflammatory destruction of the tooth-supporting alveolar bone and eventually, tooth loss. T-cell innate immune responses are actively involved in this pathological process. Receptor activator of NF-kappaB Ligand (RANKL) is a cytokine that stimulates bone resorption, while its soluble decoy receptor osteoprotegerin (OPG) blocks its action. This study aimed to investigate in Jurkat T-cells the effects of P. gingivalis on the RANKL-OPG system and the major inflammatory mediator of bone resorption prostaglandin E(2) (PGE(2)). P. gingivalis caused concentration-dependent up-regulation of RANKL gene expression and protein production, assessed by quantitative PCR and ELISA, respectively. PGE(2) production was also enhanced. However, OPG was not detected. In conclusion, P. gingivalis induces RANKL and PGE(2) in T-cells, potentially favoring bone resorption. These T-cell responses to P. gingivalis may contribute to the pathogenesis of inflammatory alveolar bone destruction occurring in chronic periodontitis. ABSTRACTPorphyromonas gingivalis is an oral pathogen highly implicated in chronic periodontitis, a disease characterised by inflammatory destruction of the toothsupporting alveolar bone, and eventually tooth loss. T-cell innate immune responses are actively involved in this pathological process. Receptor Activator of NF-κB Ligand (RANKL) is a cytokine that stimulates bone resorption, while its soluble decoy receptor osteoprotegerin (OPG) blocks its action. This study aimed to investigate in Jurkat T-cells the effects of P. gingivalis on the RANKL-OPG system and the major inflammatory mediator of bone resorption prostaglandin E 2 (PGE 2 ). P. gingivalis caused concentration-dependent up-regulation of RANKL gene expression and protein production, assessed by quantitative PCR and ELISA, respectively. PGE 2 production was also enhanced. However, OPG was not detected. In conclusion, P. gingivalis induces RANKL and PGE 2 in T-cells, potentially favouring bone resorption. These T-cell responses to P. gingivalis may contribute to the pathogenesis of inflammatory alveolar bone destruction occurring in chronic periodontitis.

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“…Importantly, studies in a murine experimental arthritis model showed that IL-17 was involved in both the initiation and the progression of the disease. Furthermore, elevated levels of IL-17 were detected in synovial fluid from patients with rheumatoid arthritis, and osteoclast formation was inhibited by anti-IL-17 antibody, suggesting an effect on bone resorption (21)(22)(23)(24)(25).…”

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confidence: 99%