Essential role of IκB kinase α in thymic organogenesis required for the establishment of self-tolerance
Essential role of IκB kinase α in thymic organogenesis required for the establishment of self-tolerance
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DOI：
10.4049/jimmunol.176.7.3995
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发表时间：
2006-04-01
影响因子：
4.4
通讯作者：
Matsumoto, Mitsuru
中科院分区：
文献类型：
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作者：
Kinoshita, Dan;Hirota, Fumiko;Matsumoto, Mitsuru
I-kappa B激酶(IKK)α通过蛋白激酶依赖和非依赖功能发挥多种生物学活性，前者主要通过非规范的核因子-kappaB激活途径介导。然而，ikkα在体内的作用仍然难以捉摸。由于带有突变的核因子-kappa B诱导激酶(NIK)的自然品系小鼠表现出自身免疫，这是胸腺结构紊乱的结果，胸腺基质中Rel蛋白的异常表达，我们推测NIK-IKKα轴可能构成建立自我耐受所需的胸腺器官发生的关键步骤。通过移植IKKα基因缺陷小鼠的胚胎胸腺，在裸鼠体内诱导了一种自身免疫性疾病表型。以IKKα依赖的方式导致自身免疫的胸腺微环境与核因子-kappaB2的处理缺陷有关，导致胸腺上皮细胞发育障碍。因此，我们的结果证明了IKKα在胸腺器官发生中的一种新的功能，即建立中枢耐受依赖于其与NIK协同的蛋白激酶活性。
I kappa B kinase (IKK) alpha exhibits diverse biological activities through protein kinase-dependent and -independent functions, the former mediated predominantly through a noncanonical NF-kappa B activation pathway. The in vivo function of IKK alpha, however, still remains elusive. Because a natural strain of mice with mutant NF-kappa B-inducing kinase (NIK) manifests autoimmunity as a result of disorganized thymic structure with abnormal expression of Rel proteins in the thymic stroma, we speculated that the NIK-IKK alpha axis might constitute an essential step in the thymic organogenesis that is required for the establishment of self-tolerance. An autoimmune disease phenotype was induced in athymic nude mice by grafting embryonic thymus from IKK alpha-deficient mice. The thymic microenvironment that caused autoimmunity in an IKK alpha-dependent manner was associated with defective processing of NF-kappa B2, resulting in the impaired development of thymic epithelial cells. Thus, our results demonstrate a novel function for IKK alpha in thymic organogenesis for the establishment of central tolerance that depends on its protein kinase activity in cooperation with NIK.