Cytotoxicity of TNFα is regulated by integrin-mediated matrix signaling
Cytotoxicity of TNFα is regulated by integrin-mediated matrix signaling
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DOI：
10.1038/sj.emboj.7601596
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发表时间：
2007-03-07
期刊：
影响因子：
11.4
通讯作者：
Lau, Lester F.
中科院分区：
文献类型：
--
作者：
Chen, Chih-Chiun;Young, Jennifer L.;Lau, Lester F.
肿瘤坏死因子（TNF）家族的细胞因子调节炎症和免疫，并且该家族的一个子集也可以以环境依赖性方式诱导细胞死亡。虽然TNF α对某些肿瘤细胞系具有细胞毒性，但只有当NF κ B信号传导被阻断时，它才能诱导正常细胞的凋亡。在这里，我们表明，基质细胞蛋白质CCN 1/CYR 61可以揭示TNF α的细胞毒性潜力，而不干扰NF κ B信号或从头蛋白合成，导致快速凋亡，否则耐药的原代人成纤维细胞。CCN 1通过与整合素α（v）β（5）、α（6）β（1）和多配体蛋白聚糖-4结合而起作用，通过Rac 1依赖性机制经由5-脂氧合酶和线粒体触发活性氧物质（ROS）的产生，导致凋亡所必需的JNK的双相活化。基因组Ccn 1基因座被细胞凋亡缺陷型Ccn 1等位基因取代的小鼠对体内TNF α诱导的细胞凋亡具有实质性抵抗力。这些结果表明，CCN 1可以作为TNF α细胞毒性的生理调节剂，提供来自TNF α介导的细胞死亡的细胞外基质的背景线索。
Cytokines of the tumor necrosis factor (TNF) family regulate inflammation and immunity, and a subset of this family can also induce cell death in a context-dependent manner. Although TNF alpha is cytotoxic to certain tumor cell lines, it induces apoptosis in normal cells only when NF kappa B signaling is blocked. Here we show that the matricellular protein CCN1/CYR61 can unmask the cytotoxic potential of TNF alpha without perturbation of NF kappa B signaling or de novo protein synthesis, leading to rapid apoptosis in the otherwise resistant primary human fibroblasts. CCN1 acts through binding to integrins alpha(v)beta(5), alpha(6)beta(1), and syndecan-4, triggering the generation of reactive oxygen species (ROS) through a Rac1-dependent mechanism via 5-lipoxygenase and the mitochondria, leading to the biphasic activation of JNK necessary for apoptosis. Mice with the genomic Ccn1 locus replaced with an apoptosis-defective Ccn1 allele are substantially resistant to TNF alpha-induced apoptosis in vivo. These results indicate that CCN1 may act as a physiologic regulator of TNF alpha cytotoxicity, providing the contextual cues from the extracellular matrix for TNF alpha-mediated cell death.