Interleukin 18 inhibits osteoclast formation via T cell production of granulocyte macrophage colony-stimulating factor

N J Horwood, N Udagawa, J Elliott, D Grail, H Okamura, M Kurimoto, A R Dunn, T Martin, M T Gillespie

Research output: Contribution to journalArticlepeer-review

197 Citations (Scopus)


IL-18 inhibits osteoclast (OCL) formation in vitro independent of IFN-gamma production, and this was abolished by the addition of neutralizing antibodies to GM-CSF. We now establish that IL-18 was unable to inhibit OCL formation in cocultures using GM-CSF-deficient mice (GM-CSF -/-). Reciprocal cocultures using either wild-type osteoblasts with GM-CSF -/- spleen cells or GM-CSF -/- osteoblasts with wild-type spleen cells were examined. Wild-type spleen cells were required to elicit a response to IL-18 indicating that cells of splenic origin were the IL-18 target. As T cells comprise a large proportion of the spleen cell population, the role of T cells in osteoclastogenesis was examined. Total T cells were removed and repleted in various combinations. Addition of wild-type T cells to a GM-CSF -/- coculture restored IL-18 inhibition of osteoclastogenesis. Major subsets of T cells, CD4+ and CD8+, were also individually depleted. Addition of either CD4+ or CD8+ wild-type T cells restored IL-18 action in a GM-CSF -/- background, while IL-18 was ineffective when either CD4+ or CD8+ GM-CSF -/- T cells were added to a wild-type coculture. These results highlight the involvement of T cells in IL-18-induced OCL inhibition and provide evidence for a new OCL inhibitory pathway whereby IL-18 inhibits OCL formation due to action upon T cells promoting the release of GM-CSF, which in turn acts upon OCL precursors.

Original languageEnglish
Pages (from-to)595-603
Number of pages9
JournalJournal of Clinical Investigation
Issue number3
Publication statusPublished - 1 Feb 1998


  • Animals
  • CD4-Positive T-Lymphocytes/drug effects
  • CD8-Positive T-Lymphocytes/drug effects
  • Cells, Cultured
  • Cytokines/pharmacology
  • Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis
  • Interferon Inducers/pharmacology
  • Interleukin-18
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoclasts/cytology
  • T-Lymphocytes/drug effects

Cite this