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

J Immunol. 2009 Aug 15;183(4):2397-406. doi: 10.4049/jimmunol.0802091. Epub 2009 Jul 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cells, Cultured
  • Down-Regulation / immunology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis*
  • Humans
  • Inflammation Mediators / metabolism
  • Inflammation Mediators / physiology
  • Interleukins / metabolism
  • Interleukins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Osteoclasts / immunology*
  • Osteoclasts / metabolism*
  • Osteoclasts / pathology
  • Proto-Oncogene Proteins c-fos / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-fos / biosynthesis
  • RANK Ligand / antagonists & inhibitors*
  • RANK Ligand / physiology*
  • Receptors, Cytokine / deficiency
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / metabolism
  • Receptors, Interleukin
  • STAT1 Transcription Factor / physiology*
  • Stem Cells / immunology
  • Stem Cells / metabolism
  • Stem Cells / pathology


  • Il27ra protein, mouse
  • Inflammation Mediators
  • Interleukins
  • MYDGF protein, human
  • Proto-Oncogene Proteins c-fos
  • RANK Ligand
  • Receptors, Cytokine
  • Receptors, Interleukin
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Granulocyte-Macrophage Colony-Stimulating Factor