Rapid up-regulation of c-FLIP expression by BCR signaling through the PI3K/Akt pathway inhibits simultaneously induced Fas-mediated apoptosis in murine B lymphocytes
Rapid up-regulation of c-FLIP expression by BCR signaling through the PI3K/Akt pathway inhibits simultaneously induced Fas-mediated apoptosis in murine B lymphocytes
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DOI：
10.1016/j.imlet.2006.12.009
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发表时间：
2007-03-15
影响因子：
4.4
通讯作者：
Yonehara, Shin
中科院分区：
文献类型：
--
作者：
Moriyama, Hiroyuki;Yonehara, Shin
BCR的交联可迅速诱导B细胞免于Fas介导的凋亡，这已被认为是抗原刺激期间B细胞的重要存活机制之一。在对Fas介导的凋亡敏感的小鼠B细胞系A20中，BCR的刺激抑制了通过caspase-8激活上游的Fas诱导的凋亡，并伴随细胞caspase-8/FLICE抑制蛋白（c-FLIP）的短形式和长形式的表达的相关快速增加。c-FLIP竞争性地抑制caspase-8向死亡诱导信号复合物（DISC）的募集，DISC在Fas刺激A20细胞后需要长达3 h才形成。通过短发夹RNA表达方法敲低c-FLIP使BCR刺激的A20细胞对Fas介导的凋亡敏感。BCR诱导的c-FLIP的快速表达不受NF-κ B失活的影响，但被PI 3 K抑制剂LY 294002或显性负性PI 3 K p85亚基的表达抑制，这两种抑制Akt的磷酸化并使BCR刺激的A20细胞对Fas介导的凋亡敏感。组成型活性Akt的过表达不仅上调c-FLIP表达，而且使A20细胞对Fas介导的凋亡具有抗性。此外，用LY 294002处理还抑制BCR诱导的脾B细胞中c-FLIP表达的上调。总之，BCR刺激显示通过促进PI 3 K/Akt信号通路介导的c-FLIP表达上调，快速触发针对同时或持续刺激的Fas介导的凋亡的存活信号。(c)2007 Elsevier B. V.保留所有权利。
Cross-linking of BCR rapidly induces protection of B cells from Fas-mediated apoptosis, which has been assumed one of the important survival mechanisms of B cells during antigen stimulation. In the mouse B cell line A20, which is sensitive to Fas-mediated apoptosis, stimulation of BCR inhibited apoptosis induced via Fas upstream of caspase-8 activation with an associated rapid increase in the expression of both short and long forms of cellular caspase-8/FLICE-inhibitory protein (c-FLIP). The c-FLIP competitively inhibited the recruitment of caspase-8 to the death-inducing signaling complex (DISC), which took as long as 3 h to form after the stimulation of Fas in A20 cells. Knockdown of c-FLIP by a short hairpin RNA-expressing method rendered BCR-stimulated A20 cells sensitive to Fas-mediated apoptosis. The BCR-induced rapid expression of c-FLIP was not affected by inactivation of NF-kappa B, but was inhibited by either treatment with a PI3K inhibitor, LY294002, or expression of a dominant negative PI3K p85 subunit, both of which suppressed phosphorylation of Akt and sensitized BCR-stimulated A20 cells to Fas-mediated apoptosis. Overexpression of constitutively active Akt was shown not only to up-regulate c-FLIP expression but also to render A20 cells resistant to Fas-mediated apoptosis. Moreover, treatment with LY294002 also suppressed BCR-induced up-regulation of c-FLIP expression in spleen B cells. Taken together, BCR-stimulation was shown to rapidly trigger a survival signal against simultaneously or ongoingly stimulated Fas-mediated apoptosis by promoting a PI3K/Akt signaling pathway-mediated up-regulation of c-FLIP expression. (c) 2007 Elsevier B.V. All rights reserved.