NF-kappaB family proteins participate in multiple steps of hematopoiesis through elimination of reactive oxygen species.
NF-kappaB family proteins participate in multiple steps of hematopoiesis through elimination of reactive oxygen species.
复制标题
DOI：
--
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Soichi Nakata;I. Matsumura;Hirokazu Tanaka;S. Ezoe;Yusuke Satoh;J. Ishikawa;T. Era;Y. Kanakura
中科院分区：
文献类型：
--
作者：
Soichi Nakata;I. Matsumura;Hirokazu Tanaka;S. Ezoe;Yusuke Satoh;J. Ishikawa;T. Era;Y. Kanakura
为了研究NF-κ B家族蛋白在造血中的作用，我们首先在因子依赖性细胞系Ba/F3中表达显性阴性Rel/NF-κ B（IkappaBSR）。虽然IkappaBSR既不影响血小板生成素依赖性也不影响gp 130介导的生长，但它在低浓度下抑制白细胞介素-3和红细胞生成素依赖性生长。此外，IkappaBSR通过活性氧（ROS）的积累增强因子剥夺的凋亡。当在正常造血干/祖细胞中表达时，IkappaBSR即使在适当的细胞因子存在下也通过积累ROS诱导凋亡。我们还使用OP 9系统在造血的各个阶段以诱导方式表达IkappaBSR，其中造血细胞被诱导从胚胎干细胞发育。当IkappaBSR在Flk-1（+）细胞（假定的成血管细胞）阶段表达时，IkappaBSR通过ROS积累诱导凋亡来抑制原始造血祖细胞的发育。此外，当IkappaBSR在造血祖细胞发育后表达时，它通过ROS积累诱导细胞凋亡来抑制它们向红细胞、巨核细胞和粒细胞的终末分化。这些结果表明，NF-κ B是通过消除ROS在造血的多个步骤中防止细胞凋亡所必需的。
To examine the roles for NF-kappaB family proteins in hematopoiesis, we first expressed dominant negative Rel/NF-kappaB(IkappaBSR) in a factor-dependent cell line, Ba/F3. Although IkappaBSR neither affected thrombopoietin-dependent nor gp130-mediated growth, it suppressed interleukin-3- and erythropoietin-dependent growth at low concentrations. In addition, IkappaBSR enhanced factor-deprived apoptosis through the accumulation of reactive oxygen species (ROS). When expressed in normal hematopoietic stem/progenitor cells, IkappaBSR induced apoptosis even in the presence of appropriate cytokines by accumulating ROS. We also expressed IkappaBSR in an inducible fashion at various stages of hematopoiesis using the OP9 system, in which hematopoietic cells are induced to develop from embryonic stem cells. When IkappaBSR was expressed at the stage of Flk-1(+) cells (putative hemangioblasts), IkappaBSR inhibited the development of primitive hematopoietic progenitor cells by inducing apoptosis through the ROS accumulation. Furthermore, when IkappaBSR was expressed after the development of hematopoietic progenitor cells, it inhibited their terminal differentiation toward erythrocytes, megakaryocytes, and granulocytes by inducing apoptosis through the ROS accumulation. These results indicate that NF-kappaB is required for preventing apoptosis at multiple steps of hematopoiesis by eliminating ROS.