IL-27 abrogates receptor activator of NF-κB ligand-mediated osteoclastogenesis of human granulocyte-macrophage colony-forming unit cells through STAT1-dependent inhibition of c-Fos

Mitsuru Furukawa, Hironari Takaishi, Jiro Takito, Masaki Yoda, Sadaoki Sakai, Tomohiro Hikata, Akihiro Hakozaki, Shinichi Uchikawa, Morio Matsumoto, Kazuhiro Chiba, Tokuhiro Kimura, Yasunori Okada, Koichi Matsuo, Hiroki Yoshida, Yoshiaki Toyama

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43 Citations (Scopus)

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-27Rα (WSX-1)/gp130 heterodimer. Cultivation in hM-CSF and human receptor activator of NF-κB 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-κB 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.

Original languageEnglish
Pages (from-to)2397-2406
Number of pages10
JournalJournal of Immunology
Volume183
Issue number4
DOIs
Publication statusPublished - 2009 Aug 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Furukawa, M., Takaishi, H., Takito, J., Yoda, M., Sakai, S., Hikata, T., Hakozaki, A., Uchikawa, S., Matsumoto, M., Chiba, K., Kimura, T., Okada, Y., Matsuo, K., Yoshida, H., & Toyama, Y. (2009). IL-27 abrogates receptor activator of NF-κB ligand-mediated osteoclastogenesis of human granulocyte-macrophage colony-forming unit cells through STAT1-dependent inhibition of c-Fos. Journal of Immunology, 183(4), 2397-2406. https://doi.org/10.4049/jimmunol.0802091