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T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ

机译：T细胞介导的破骨细胞生成调控，通过信号传导RANKL和IFN-γ之间的串扰

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摘要

Bone resorption is regulated by the immune system, where T-cell expression of RANKL (receptor activator of nuclear factor (NF)-κB ligand), a member of the tumour-necrosis factor family that is essential for osteodastogenesis, 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)-γ strongly suppresses osteodastogenesis by interfering with the RANKL-RANK signalling pathway. IFN-γ 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-κB and JNK. This inhibition of osteodastogenesis is rescued by over-expressing TRAF6 in precursor cells, which indicates that TRAF6 is the target critical for the IFN-γ action. Furthermore, we provide evidence that the accelerated degradation of TRAF6 requires both its ubiquitination, which is initiated by RANKL, and IFN-γ-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-γ 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.
机译：骨吸收受到免疫系统的调节，RANKL（核因子（NF）-κB配体的受体激活剂）（对骨形成的形成至关重要的肿瘤坏死因子家族的成员）的T细胞表达可能在其中起作用。如自身免疫性关节炎。但是，激活的T细胞是否通过平衡RANKL的作用来维持骨稳态仍是未知的。在这里，我们显示干扰素（IFN）-γ的T细胞产生可通过干扰RANKL-RANK信号传导途径强烈抑制成骨细胞生成。 IFN-γ诱导RANK衔接子蛋白TRAF6（肿瘤坏死因子受体相关因子6）快速降解，从而强烈抑制RANKL诱导的转录因子NF-κB和JNK的激活。通过在前体细胞中过度表达TRAF6可以挽救这种对骨形成不良的抑制作用，这表明TRAF6是IFN-γ作用的关键靶标。此外，我们提供的证据表明，TRAF6的加速降解既需要其泛素化（由RANKL启动），又需要IFN-γ诱导的泛素-蛋白酶体系统活化。我们的研究表明，肿瘤坏死因子与细胞因子IFN家族之间存在相互影响，通过IFN-γ，T细胞活化与骨吸收之间存在负相关关系。我们的结果可能提供治疗炎症引起的组织破裂的治疗方法。

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