title: IFN-γ directly inhibits TNF-α-induced osteoclastogenesis in vitro and in vivo and induces apoptosis mediated by Fas/Fas ligand interactions.
abstract: Cytokines secreted by T cells play a pivotal role in inflammatory bone destruction. Tumor necrosis factor-α (TNF-α) is a major proinflammatory cytokine produced by macrophages following T cell activation, and directly promotes osteoclast differentiation resulting in accelerated bone resorption. Interferon-γ (IFN-γ) attenuates RANKL-initiated cellular signals through osteoclast formation and counterbalances aberrant bone resorption. With respect to this crosstalk during osteoclastogenesis, the direct interruption of IFN-γ in TNF-α-induced osteoclast formation still requires elucidation. We have demonstrated that IFN-γ directly inhibits osteoclastogenesis induced by TNF-α stimulation and accelerates apoptosis mediated by Fas/Fas ligand signals. There were a decreased number of osteoclasts and reduced mRNA levels encoding Nfatc1 in cultured bone marrow macrophages. Apoptotic responses of cultured cells were observed, with accelerated nuclear fragmentation in osteoclast precursor cells and increased FasL mRNA levels in bone marrow cells stimulated with TNF-α evident. IFN-γ reduced the level of osteoclastogenesis in response to TNF-α treatment in vivo. IFN-γ inhibited TNF-α-induced osteoclastogenesis in mice with T cells that had been exposed to anti-CD4 and -CD8 antibodies. These results provide evidence that IFN-γ directly inhibits osteoclastogenesis and induces cells apoptosis by Fas/FasL signals, leading to the indirect regulation of bone resorption, which is required for protective roles in bone destruction at an inflammation site.
authors.affiliation: Department of Orthodontics and Dentofacial Orthopedics, Nagasaki University Graduate School of Biomedical Sciences, Japan. dm07002h@cc.nagasaki-u.ac.jp
authors.forename: Haruka
authors.initials: H
authors.lastname: Kohara
authors.forename: Hideki
authors.initials: H
authors.lastname: Kitaura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Fujimura
authors.forename: Masako
authors.initials: M
authors.lastname: Yoshimatsu
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Morita
authors.forename: Toshiko
authors.initials: T
authors.lastname: Eguchi
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Masuyama
authors.forename: Noriaki
authors.initials: N
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001862:Bone Resorption / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D053222:Fas Ligand Protein; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma