TRAIL receptor mediates inflammatory cytokine release in an NF-kappaB-dependent manner.
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-1beta in an NF-kappaB-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-IKKalpha/beta signaling cascade, which plays an essential role in TNF-induced NF-kappaB 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-kappaB activation and cytokine secretion and crosstalks with the TRADD-TRAF2-NIK-IKKalpha/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.
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Wanhu
W
Tang
Weimin
W
Wang
Yaxi
Y
Zhang
Shilian
S
Liu
Yanxin
Y
Liu
Dexian
D
Zheng
D017209:Apoptosis; D002460:Cell Line; D054418:Chemokine CCL20 / Q000378:metabolism; D054407:Chemokine CCL4 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C066507:CCL4 protein, human; D054418:Chemokine CCL20; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D016207:Cytokines; D016209:Interleukin-8; D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha