Interleukin 18 inhibits osteoclast formation via T cell production of granulocyte macrophage colony-stimulating factor
Interleukin 18 inhibits osteoclast formation via T cell production of granulocyte macrophage colony-stimulating factor
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DOI：
10.1172/jci1333
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发表时间：
1998-02-01
影响因子：
15.9
通讯作者：
Gillespie, MT
中科院分区：
文献类型：
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作者：
Horwood, NJ;Udagawa, N;Gillespie, MT
IL-18在体外抑制破骨细胞（OCL）的形成，而不依赖于IFN-γ的产生，并且这被添加针对GM-CSF的中和抗体所消除。我们现在确定，在使用GM-CSF缺陷型小鼠（GM-CSF -/-）的共培养物中，IL-18不能抑制OCL的形成。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。去除总T细胞并以各种组合补充。向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。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细胞恢复了IL-18在GM-CSF -/-背景下的作用，而当将CD 4（+）或CD 8（+）GM-CSF -/- T细胞加入野生型共培养物中时，IL-18无效。这些结果突出了T细胞参与IL-18诱导的OCL抑制，并为新的OCL抑制途径提供了证据，其中IL-18抑制OCL形成，这是由于对T细胞的作用促进了GM-CSF的释放，而GM-CSF又作用于OCL前体。
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(+) wildtype 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.