TRAIL receptor mediates inflammatory cytokine release in an NF-κB-dependent manner
TRAIL receptor mediates inflammatory cytokine release in an NF-κB-dependent manner
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DOI：
10.1038/cr.2009.57
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发表时间：
2009-06-01
期刊：
影响因子：
44.1
通讯作者：
Zheng, Dexian
中科院分区：
文献类型：
--
作者：
Tang, Wanhu;Wang, Weimin;Zheng, Dexian
在这篇文章中，我们报告了DR 4或DR 5过表达在293 T、MDA-MB-231和HCT-116细胞中以NF-κ B依赖的方式显著激活炎性细胞因子IL-8、TNF-α、CCL 20、MIP-2和MIP-1 β的释放。我们发现，死亡受体介导的信号是细胞外结构域的独立性，而DR 4细胞内结构域的过表达的效果是弱得多。TRADD-TRAF 2-NIK-IKK α/β信号级联在TNF诱导的NF-κ B活化中起重要作用，被发现参与肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体介导的信号转导。FADD-半胱天冬酶信号通路，据报道主要与细胞凋亡相关，被鉴定为DR 4或DR 5过表达介导的NF-κ B活化和细胞因子分泌以及TRADD-TRAF 2-NIK-IKK α/β信号级联的串扰所必需。此外，DR 5激动性抗体（AD 5 -10）触发炎性细胞因子释放。这些数据，加上以前的报告，提供了强有力的证据表明，TRAIL和TRAIL受体在炎症中发挥重要作用。
In the present article, we report that DR4 or DR5 overexpression dramatically activates the release of the inflammatory cytokines IL-8, TNF-alpha, CCL20, MIP-2 and MIP-1 beta in an NF-kappa B-dependent manner in 293T, MDA-MB-231 and HCT-116 cells. We showed that death receptor-mediated signals were extracellular domain-independent, whereas the effect of overexpression of the DR4 intracellular domain was much less potent. The TRADD-TRAF2-NIK-IKK alpha/beta signaling cascade, which plays an essential role in TNF-induced NF-kappa B activation, was found to be involved in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated signal transduction. The FADD-caspase signaling pathway, which has been reported to be mostly related to apoptosis, was identified as being essential for DR4 or DR5 overexpression-mediated NF-kappa B activation and cytokine secretion and crosstalks with the TRADD-TRAF2-NIK-IKK alpha/beta signaling cascade. Furthermore, a DR5 agonistic antibody (AD5-10) triggered the inflammatory cytokine release. These data, together with previous reports, provide strong evidence that TRAIL and TRAIL receptors play an important role in inflammation.