ORIGINAL ARTICLE

Cell Research (2009): 758-767
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TRAIL receptor mediates inflammatory cytokine release in an NF-κB-dependent manner

Wanhu Tang, Weimin Wang, Yaxi Zhang, Shilian Liu, Yanxin Liu1 and Dexian Zheng

Correspondence: Dexian Zheng or Yanxin Liu, Tel: +8610 6529 6409; Fax: +8610 6510 5102 E-mail: zhengdx@tom.com

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In the present article, we report that DR4 or DR5 overexpression dramatically activates the release of the inflammatory cytokines IL-8, TNF-α, CCL20, MIP-2 and MIP-1β in an NF-κB-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-IKKα/β signaling cascade, which plays an essential role in TNF-induced NF-κB 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-κB activation and cytokine secretion and crosstalks with the TRADD-TRAF2-NIK-IKKα/β 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.

Cell Research (2009) 19:758–767. doi: 10.1038/cr.2009.57; published online 12 May 2009

Keywords: TRAIL receptor, inflammation, cytokine, NF-κB