Abstract
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 language | English |
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Pages (from-to) | 595-603 |
Number of pages | 9 |
Journal | Journal of Clinical Investigation |
Volume | 101 |
Issue number | 3 |
DOIs | |
Publication status | Published - 1 Feb 1998 |
Keywords
- 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