Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K, Nakamura K, Taniguchi T
Department of Immunology, Faculty of Medicine and Graduate School of Medicine, University of Tokyo, Japan.
Nature. 2000 Nov 30;408(6812):600-5. doi: 10.1038/35046102.
Bone resorption is regulated by the immune system, 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. 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.
骨吸收受免疫系统调节，其中肿瘤坏死因子家族成员核因子κB受体激活配体（RANKL）的T细胞表达对破骨细胞生成至关重要，可能导致自身免疫性关节炎等病理状况。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不清楚。在此我们表明，T细胞产生的干扰素γ（IFN-γ）通过干扰RANKL-RANK信号通路强烈抑制破骨细胞生成。IFN-γ诱导RANK衔接蛋白肿瘤坏死因子受体相关因子6（TRAF6）快速降解，导致RANKL诱导的转录因子核因子κB和JNK活化受到强烈抑制。在前体细胞中过表达TRAF6可挽救这种对破骨细胞生成的抑制，这表明TRAF6是IFN-γ作用的关键靶点。此外，我们提供证据表明，TRAF6的加速降解既需要RANKL引发的其泛素化，也需要IFN-γ诱导的泛素-蛋白酶体系统活化。我们的研究表明，肿瘤坏死因子和细胞因子IFN家族之间存在相互作用，通过这种相互作用，IFN-γ在T细胞活化和骨吸收之间提供了一个负向联系。我们的结果可能为治疗炎症诱导的组织破坏提供一种治疗方法。
