INTERLEUKIN-18 INHIBITS OSTEOCLAST FORMATION VIA T-CELL PRODUCTION OFGRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR

IL-18 inhibits osteoclast (OCL) formation in vitro independent of IFN- gamma production, and this was abolished by the addition of neutralizi ng antibodies to GM-CSF, We now establish that IL-18 was unable to inh ibit 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 c ells were examined. Wild-type spleen cells were required to elicit a r esponse to IL-18 indicating that cells of splenic origin were the IL-1 8 target. As T cells comprise a large proportion of the spleen cell po pulation, the role of T cells in osteoclastogenesis was examined. Tota l T cells were removed and repleted in various combinations, Addition of wild-type T cells to a GM-CSF -/- coculture restored IL-18 inhibiti on of osteoclastogenesis, Major subsets of T cells, CD4(+) and CD8(+), were also individually depleted, Addition of either CD4(+) or CD8(+) wildtype T cells restored IL-18 action in a GM-CSF -/- background, whi le IL-18 was ineffective when either CD4(+) or CD8(+) GM-CSF -/- T cel ls were added to a wild-type coculture. These results highlight the in volvement of T cells in IL-18-induced OCL inhibition and provide evide nce for a new OCL inhibitory pathway whereby IL-18 inhibits OCL format ion due to action upon T cells promoting the release of GM-CSF, which in turn acts upon OCL precursors.