title: IL-27 abrogates receptor activator of NF-kappa B ligand-mediated osteoclastogenesis of human granulocyte-macrophage colony-forming unit cells through STAT1-dependent inhibition of c-Fos.
abstract: IL-27 was first discovered as a factor supporting initial Th1 immune responses. Subsequent studies revealed that this cytokine has pleiotropic effects, including inhibition of certain immune cells, a regulatory role in hemopoietic stem cell differentiation, and antitumor activities. However, the role of human IL (hIL)-27 in human osteoclast precursors and inflammatory bone disease is unclear. Here, we examined the direct effect of hIL-27 on human osteoclastogenesis. Human bone marrow cells cultured in MethoCult medium containing human (h) GM-CSF, human stem cell factor, and hIL-3 expressed Mac-1, c-kit, and c-Fms. These cells, called hCFU-GMs, also expressed the IL-27 receptor, an IL-27Ralpha (WSX-1)/gp130 heterodimer. Cultivation in hM-CSF and human receptor activator of NF-kappaB ligand induced the differentiation of tartrate-resistant acid phosphatase-positive multinucleated cells (osteoclasts) from hCFU-GMs, and hIL-27 inhibited this osteoclastogenesis in a dose-dependent manner. hIL-27 also repressed bone resorption by osteoclasts on a dentine slice. hIL-27 caused a remarkable increase in STAT1 phosphorylation and enhanced the STAT1 protein level. It also inhibited the expression of receptor activator of NF-kappaB ligand-induced c-Fos and cytoplasmic, calcineurin-dependent 1 NFAT (NFATc1), which are indispensable transcription factors for osteoclastogenesis. Fludarabine, a STAT1 inhibitor, and STAT1 small interfering RNA partially rescued the inhibition of osteoclastogenesis by IL-27. A WSX-1 deficiency caused severe inflammatory bone destruction primed by Escherichia coli cell wall lysate in vivo. Therefore, hIL-27 may act as an anti-inflammatory cytokine in human bone destruction, by inhibiting osteoclastogenesis from hCFU-GMs via STAT1-dependent down-regulation of the transcription factor c-Fos. Our results suggest that hIL-27 may prove useful as a therapeutic target for inflammatory bone destruction.
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Furukawa
authors.forename: Hironari
authors.initials: H
authors.lastname: Takaishi
authors.forename: Jiro
authors.initials: J
authors.lastname: Takito
authors.forename: Masaki
authors.initials: M
authors.lastname: Yoda
authors.forename: Sadaoki
authors.initials: S
authors.lastname: Sakai
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Hikata
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hakozaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchikawa
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Chiba
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Kimura
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D007378:Interleukins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010010:Osteoclasts / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000502:physiology*; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor / Q000502:physiology*; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: C484747:Il27ra protein, mouse; D018836:Inflammation Mediators; D007378:Interleukins; C464565:MYDGF protein, human; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D016178:Granulocyte-Macrophage Colony-Stimulating Factor