Mechanism of osteoclastogenesis inhibitory action by interleukin 18

IL-18在体外抑制破骨细胞（CCL）的形成，而不依赖于IFN-γ的产生，这一点可通过加入GM-CSF的中和抗体来消除。检查了使用野生型成骨细胞与GM-CSF -/-脾细胞或GM-CSF -/-成骨细胞与野生型脾细胞的相互共培养物。需要野生型脾细胞来引发对IL-18的应答，表明脾来源的细胞是IL-18靶标。由于T细胞在脾细胞群中占很大比例，因此检查了T细胞在破骨细胞生成中的作用。取出总T细胞并以各种组合补充。在GM-CSF -/-共培养物中加入野生型T细胞恢复了IL-18对破骨细胞生成的抑制作用。T细胞的主要亚群，CD 4和CD 8 +^+，也被单独耗尽。加入CD 4 ^+或CD 8 ^+野生型T细胞可以恢复IL-18在GM-CSF -/-背景下的作用，而当加入CD 4 ^+或CD 8 ^+ GM-CSF -/- T细胞到野生型共培养物中时，IL-18则无效。这些结果突出了T细胞参与IL-18诱导的CCL抑制，并为新的CCL抑制途径提供了证据，其中IL-18抑制CCL形成，这是由于对T细胞的作用促进了GM-CSF的释放，GM-CSF又作用于CCL前体。

IL-18 inhibits osteoclast (CCL) 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 CCL 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, 0D4 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 CCL inhibition and provide evidence for a new CCL inhibitory pathway whereby IL-18 inhibits CCL formation due to action upon T cells promoting the release of GM-CSF, which in turn acts upon CCL precursors.