Regulation of immune responses by NF-kappa B/Rel transcription factor.
Regulation of immune responses by NF-kappa B/Rel transcription factor.
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DOI：
10.1084/jem.187.2.143
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发表时间：
1998-01-19
期刊：
影响因子：
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通讯作者：
Sha WC
中科院分区：
文献类型：
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作者：
Sha WC
在外周淋巴器官内，在对抗原的免疫反应过程中，淋巴细胞和抗原呈递细胞之间发生复杂的相互作用。尽管人们相当多地认识到先天免疫信号通路的激活对于产生有效的适应性免疫反应是必要的，但对于如何在分子水平上实现这种协调仍然有很多未知。 NF-κB/Rel 转录因子在过去几年中一直是人们极大兴趣的焦点，部分原因是它们似乎处于整合先天性和适应性免疫信号通路信息的理想位置。基因靶向敲除小鼠的最新进展表明 NFκB/Rel 转录因子是抗原呈递细胞和淋巴细胞水平免疫反应的关键调节因子。 NF-κB/Rel 转录因子以二聚体的形式发挥作用，通过抑制剂 IκB 蛋白家族潜伏在细胞的细胞质中（综述参见参考文献 1-3）。有五种已知的哺乳动物 NF-κB/Rel 蛋白：Rel (c-Rel)、p65 (RelA)、RelB、p50 (NFKB1) 和 p52 (NFKB2)。 p50 的 p105 前体和 p52 的 p100 前体都具有 IκB 功能域，并且存在至少五种不同的 IκB 蛋白：IκBα、IκBß、IκBε、IκB 和 bcl-3。NF-κB/Rel 转录因子由参与免疫功能和发育的多种不同信号通路激活。参与激活这些因子的先天免疫反应的信号通路包括新发现的果蝇 Toll 人类同源物 (4)、细胞因子 TNF-α 和 IL-1α、趋化肽 fMet-Leu-Phe (5) 以及各种不同的细菌和病毒产物 (1-3)。参与激活这些因子的适应性免疫反应的信号通路包括关键的淋巴细胞受体信号通路，例如 B 和 T 细胞上的抗原受体、T 细胞上的 CD28 和 B 细胞上的 CD40 (1-3)。这些信号通路集中在 IκB 的磷酸化和降解上，从而揭示核定位信号，导致 NF-κB/Rel 二聚体易位到细胞核中。最近，已经鉴定了几种参与 IκB 磷酸化的激酶，对这些长期寻求的 IκB 激酶的研究应该可以为 NF-κB/Rel 转录因子激活的调节提供重要的见解 (6-12)。
Within peripheral lymphoid organs, complex interac-tions occur between lymphocytes and antigen-presenting cells during an immune response to antigen. Although there is considerable recognition of the fact that activation of innate immune signaling pathways is necessary for productive adaptive immune responses to occur, a great deal is still unknown about how this coordination is achieved at a molecular level. NF-κB/Rel transcription factors have been the focus of considerable interest over the past few years, in part because they seem ideally positioned to integrate information from both innate and adaptive immune signaling pathways. Recent develoments with genetargeted knockout mice indicate that NFκB/Rel transcription factors are critical regulators of immune responses at the level of both antigen-presenting cells and lymphocytes. NF-κB/Rel transcription factors function as dimers held latently in the the cytoplasm of cells by a family of inhibitor IκB proteins (for reviews see references 1–3). There are five known mammalian NF-κB/Rel proteins: Rel (c-Rel), p65 (RelA), RelB, p50 (NFKB1), and p52 (NFKB2). Both the p105 precursor of p50, and the p100 precursor of p52, possess domains that function as IκBs, and there exist at least five distinct IκB proteins: IκBα, IκBß, IκBε, IκB, and bcl-3.NF-κB/Rel transcription factors are activated by a surprising variety of different signaling pathways involved in immune function and development. Signaling pathways involved in innate immune responses that activate these factors include a newly identified human homologue of Drosphila Toll (4), the cytokines TNF-α and IL-1α, the chemotactic peptide fMet-Leu-Phe (5), as well a variety of different bacterial and viral products (1–3). Signaling pathways involved in adaptive immune responses that activate these factors include key lymphocyte receptor signaling pathways such as antigen receptors on B and T cells, CD28 on T cells, and CD40 on B cells (1–3). These signaling pathways converge on phosphorylation and degradation of IκBs, which unmask a nuclear localization signal that leads to translocation of NF-κB/Rel dimers into the nucleus. Recently, several of the kinases involved in phosphorylation of IκBs have been identified, and studies of these long sought after IκB kinases should provide significant insight into the regulation of activation of NF-κB/Rel transcription factors (6–12).