T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ
T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ
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DOI：
10.1038/35046102
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发表时间：
2000-11-30
期刊：
影响因子：
64.8
通讯作者：
Taniguchi, T
中科院分区：
文献类型：
--
作者：
Takayanagi, H;Ogasawara, K;Taniguchi, T
骨吸收受免疫系统调节（1，2），其中RANKL（核因子（NF）-kappaB配体的受体激活剂）的T细胞表达，是破骨细胞生成所必需的肿瘤坏死因子家族的成员，可能导致病理状况，如自身免疫性关节炎（3，4）。然而，活化的T细胞是否通过平衡RANKL的作用来维持骨稳态仍然未知。在这里，我们表明，T细胞产生的干扰素（IFN）-γ强烈抑制破骨细胞通过干扰RANKL-RANK信号通路。IFN-γ诱导RANK衔接蛋白TRAF 6（肿瘤坏死因子受体相关因子6）快速降解，导致RANKL诱导的转录因子NF-κ B和JNK活化受到强烈抑制。这种对破骨细胞生成的抑制通过在前体细胞中过表达TRAF 6来挽救，这表明TRAF 6是IFN-γ作用的关键靶标。此外，我们提供的证据表明，TRAF 6的加速降解需要其泛素化，这是由RANKL启动，和IFN-γ诱导的泛素-蛋白酶体系统的激活。我们的研究表明，在肿瘤坏死因子和IFN家族的细胞因子之间存在串扰，通过这种串扰，IFN-γ在T细胞活化和骨吸收之间提供了负性联系。我们的研究结果可能为治疗炎症诱导的组织破坏提供一种治疗方法。
Bone resorption is regulated by the immune system(1,2), where T-cell expression of RANKL (receptor activator of nuclear factor (NF)-kappaB ligand), a member of the tumour-necrosis factor family that is essential for osteoclastogenesis, may contribute to pathological conditions, such as autoimmune arthritis(3,4). However, whether activated T cells maintain bone homeostasis by counterbalancing the action of RANKL remains unknown. Here we show that T-cell production of interferon (IFN)-gamma strongly suppresses osteoclastogenesis by interfering with the RANKL-RANK signalling pathway. IFN-gamma induces rapid degradation of the RANK adapter protein, TRAF6 (tumour necrosis factor receptor-associated factor 6), which results in strong inhibition of the RANKL-induced activation of the transcription factor NF-kappaB and JNK. This inhibition of osteoclastogenesis is rescued by overexpressing TRAF6 in precursor cells, which indicates that TRAF6 is the target critical for the IFN-gamma action. Furthermore, we provide evidence that the accelerated degradation of TRAF6 requires both its ubiquitination, which is initiated by RANKL, and IFN-gamma -induced activation of the ubiquitin-proteasome system. Our study shows that there is cross-talk between the tumour necrosis factor and IFN families of cytokines, through which IFN-gamma provides a negative link between T-cell activation and bone resorption. Our results may offer a therapeutic approach to treat the inflammation-induced tissue breakdown.