Mechanism of osteoclastogenesis inhibitory action by interleukin 18

IL-18在体外抑制破骨细胞(CCL)的形成，不依赖于干扰素-γ的产生，这种抑制作用可被GM-CSF的中和抗体所取消。我们现在发现，在GM-CSF缺陷小鼠(GM-CSF-/-)的共同培养中，IL-18不能抑制CCL的形成。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相互共培养。野生型脾细胞被要求对IL-18产生反应，这表明脾来源的细胞是IL-18的靶标。由于T细胞在脾细胞群中占很大比例，因此对T细胞在破骨细胞形成中的作用进行了研究。全部T细胞被取出，并以不同的组合重新加入。在GM-CSF-/-共培养中加入野生型T细胞可恢复IL-18对破骨细胞生成的抑制作用。T细胞的主要亚群0D4和CD8^也分别被耗尽。加入CD4^或CD8^野生型T细胞可在GM-CSF-/-背景下恢复IL-18的活性，而当加入CD4^或CD8^GM-CSF-/-T细胞时，IL-18则无效。这些结果突出了T细胞参与了IL-18诱导的CCL抑制，并为IL-18通过作用于T细胞促进GM-CSF的释放进而作用于CCL前体而抑制CCL的形成提供了新的证据。

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.