Non-apoptotic signaling pathways activated by soluble Fas ligand in serum-starved human fibroblasts -: Mitogen-activated protein kinases and NF-κB-dependent gene expression
Non-apoptotic signaling pathways activated by soluble Fas ligand in serum-starved human fibroblasts -: Mitogen-activated protein kinases and NF-κB-dependent gene expression
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DOI：
10.1074/jbc.m107385200
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发表时间：
2001-12-14
影响因子：
4.8
通讯作者：
Lee, TH
中科院分区：
文献类型：
--
作者：
Ahn, JH;Park, SM;Lee, TH
许多表达Fas的细胞在Fas刺激下不发生细胞死亡。在正常的人二倍体细胞系GM6112中，添加可溶性Fas配体（sFasL）导致不到1%的细胞出现细胞死亡的形态学迹象。用sFasL处理血清饥饿的GM6112成纤维细胞导致ERK1/2的快速和短暂磷酸化，而JNK和p38活性未显着增加。除非与蛋白质合成抑制剂anisomycin共同处理，否则sFasL在完全培养基中维持的细胞中不表现出基因诱导活性。然而，当细胞血清饥饿4天时，sFasL单独处理可诱导白细胞介素-6基因表达，而白细胞介素-8基因表达的作用较弱。血清饥饿对基因诱导活性的增敏与sFasL激活NF-kappaB相关。此外，我们发现血清饥饿细胞中FADD和caspase-8的表达显著降低，而cFLIP的表达水平保持不变。转染反义caspase-8表达的GM6112细胞可使细胞对sfasl诱导的nf - kappab依赖性报告细胞激活敏感。我们的研究结果支持这样一种观点，即cFLIP和caspase-8比例的变化可能负责打开fas激活的NF-kappaB途径，否则该途径将被诱导死亡的途径所取代。
Many Fas-expressing cells do not undergo cell death upon Fas stimulation. In the normal human diploid cell line GM6112, the addition of soluble Fas ligand (sFasL) leads to morphological signs of cell death in less than 1% of cells. Treatment of serum-starved GM6112 fibroblasts with sFasL resulted in a rapid and transient phosphorylation of ERK1/2 without a significant increase in JNK and p38 activities. Unless co-treated with the protein synthesis inhibitor anisomycin, sFasL did not show gene-inducing activity in cells maintained in complete medium. However, when cells were serum-starved for 4 days, treatment with sFasL alone induced interleukin-6 gene expression and, less strongly, interleukin-8 gene expression. Sensitization of the gene-inducing activity by serum starvation correlated with NF-kappaB activation by sFasL. Furthermore, we found that the expression of FADD and caspase-8 was significantly reduced in serum-starved cells, whereas the level of cFLIP remained unchanged. Transfection of GM6112 cells with the antisense caspase-8 expression construct sensitized cells toward sFasL-induced NF-kappaB-dependent reporter activation. Our results support the notion that a change in the ratio of cFLIP and caspase-8 may be responsible for turning on the Fas-activated NF-kappaB pathway, which otherwise is supplanted by the death-inducing pathway.