NF-kB inhibitor blocks B cell development at two checkpoints.
NF-kB inhibitor blocks B cell development at two checkpoints.
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DOI：
10.1186/1476-9433-3-1
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发表时间：
2004-03-29
期刊：
影响因子：
--
通讯作者：
Liou, Hsiou-Chi
中科院分区：
文献类型：
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作者：
Feng, Biao;Cheng, Shuhua;Liou, Hsiou-Chi
NF-kB转录因子家族的成员在B细胞谱系中有差异表达。单个或两个NF-kB亚基的破坏在B淋巴细胞的发育、激活和存活中表现出明显的缺陷。然而，每种NF-kB在B细胞发育过程中所起的作用被分子补偿所掩盖。为了解决这个问题，利用逆转录病毒系统将IkBalpha的反显性形式转导到骨髓细胞中，作为NF-kB的泛抑制剂。虽然t淋巴细胞和髓系细胞的发育没有受到IkBalpha基因转导的严重影响，但在IkBalpha转导的嵌合小鼠中，B系细胞的数量和百分比明显减少。IkBalpha的表达降低了骨髓中预B细胞和未成熟B细胞亚群的百分比，并进一步损害了外周血泡成熟B细胞和边缘带B细胞的发育。Bcl-X转基因的引入完全恢复了骨髓中的前B细胞和未成熟B细胞池。然而，尽管B细胞谱系的整体活力显著提高，但Bcl-X的表达不足以克服NF-kB抑制导致的成熟障碍。总之，我们的研究表明，NF-kB活性在B细胞发育过程中需要两个不同的检查点：一个是前B细胞/未成熟B细胞的活力，另一个是提供生存和成熟信号，以确保滤泡成熟B细胞的正常发育。
Members of the NF-kB transcription factor family are differentially expressed in the B cell lineage. Disruption of individual or two NF-kB subunits exhibits distinct defects in B lymphocyte development, activation, and survival. However, the role each NF-kB plays during B cell development has been obscured by molecular compensation. To address this issue, a trans-dominant form of IkBalpha was transduced into bone marrow cells to act as a pan-inhibitor of NF-kB using a retroviral system. While the development of T-lymphocytes and myeloid cell lineages was not grossly affected by the transduced IkBalpha gene, a significant reduction in the number and percentage of B lineage cells was apparent in IkBalpha transduced chimeric mice. IkBalpha expression decreased the percentage of pre-B and immature B cell subsets in the bone marrow and further impaired the development of follicular mature B cells and marginal zone B cells in the periphery. Introduction of the Bcl-X transgene completely restored the pre-B and immature B cell pool in the bone marrow. However, despite a significant improvement of overall viability of the B cell lineage, Bcl-X expression was insufficient to overcome the maturation block resulting from NF-kB inhibition. Together, our study suggests that NF-kB activity is required for two distinct checkpoints during B cell development: one is for pre-B/immature B cell viability, the other is to provide both survival and maturation signals to ensure the proper development of follicular mature B cells.