Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, Nakao K, Nakamura K, Katsuki M, Yamamoto T, Inoue J
Department of Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Genes Cells. 1999 Jun;4(6):353-62. doi: 10.1046/j.1365-2443.1999.00265.x.
TRAF6, a member of the tumour necrosis factor receptor-associated factor family, was first identified as a transducer of CD40 and interleukin-1 receptor (IL-1R) signals based on the interaction of TRAF6 with the cytoplasmic tail of CD40 and with the IL-1R associated kinase in vitro. However, the functions of TRAF6 in vivo remain unidentified.
We show that TRAF6-/- mice exhibit severe osteopetrosis and are defective in osteoclast formation. In vitro culture experiments revealed that osteoclast precursor cells derived from TRAF6-/- mice are unable to differentiate to functional osteoclasts in response to osteoclast differentiation factor (ODF). In bone marrow of TRAF6-/- mice, the number of sIgM+B220+ immature B cells is markedly reduced while the ratio of proB to preB cells is not affected. In contrast, development of thymocytes is not affected. Furthermore, TRAF6-/- mice are defective in lymph node organogenesis and IL-1 signalling in thymocytes.
The results identify TRAF6 as an essential component of ODF signalling pathway, and also show that TRAF6 plays pivotal roles in immune and inflammatory systems in vivo.
肿瘤坏死因子受体相关因子家族成员TRAF6，最初是基于其在体外与CD40胞质尾以及白细胞介素-1受体相关激酶的相互作用，而被鉴定为CD40和白细胞介素-1受体（IL-1R）信号的转导分子。然而，TRAF6在体内的功能仍未明确。
我们发现TRAF6基因敲除小鼠表现出严重的骨质石化，破骨细胞形成存在缺陷。体外培养实验表明，源自TRAF6基因敲除小鼠的破骨细胞前体细胞无法响应破骨细胞分化因子（ODF）分化为功能性破骨细胞。在TRAF6基因敲除小鼠的骨髓中，表面免疫球蛋白M阳性（sIgM+）B220+未成熟B细胞数量显著减少，而前B细胞与前前B细胞的比例不受影响。相比之下，胸腺细胞的发育不受影响。此外，TRAF6基因敲除小鼠在淋巴结器官发生和胸腺细胞中的IL-1信号传导方面存在缺陷。
这些结果确定TRAF6是ODF信号通路的重要组成部分，并且还表明TRAF6在体内免疫和炎症系统中起关键作用。
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