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TRAIL receptor mediates inflammatory cytokine release in an NF-kappaB-dependent manner

Wanhu Tang1, Weimin Wang, Yaxi Zhang

  • 1National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Cell Research
|May 13, 2009
PubMed

Insights

Overexpression of death receptors DR4 or DR5 activates inflammatory cytokine release via NF-kappaB signaling. This pathway involves crosstalk between FADD-caspase and TRADD-TRAF2-NIK-IKK signaling cascades, highlighting the role of TRAIL receptors in inflammation.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Biology

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors (DR4 and DR5) are known for their role in apoptosis.
  • NF-kappaB signaling is a key pathway regulating inflammatory responses.

Purpose of the Study:

  • To investigate the role of DR4 and DR5 in inflammatory cytokine release.
  • To elucidate the signaling pathways involved in DR4/DR5-mediated inflammation.

Main Methods:

  • Overexpression of DR4 and DR5 in 293T, MDA-MB-231, and HCT-116 cells.
  • Analysis of inflammatory cytokine release (IL-8, TNF-alpha, CCL20, MIP-2, MIP-1beta).
  • Investigation of NF-kappaB-dependent signaling pathways, including TRADD-TRAF2-NIK-IKK and FADD-caspase cascades.

Main Results:

  • DR4 or DR5 overexpression dramatically activated the release of multiple inflammatory cytokines in an NF-kappaB-dependent manner.
  • Death receptor-mediated signals were extracellular domain-independent, with less potency from DR4 intracellular domain overexpression.
  • The TRADD-TRAF2-NIK-IKKalpha/beta and FADD-caspase signaling pathways were both essential and showed crosstalk in DR4/DR5-mediated NF-kappaB activation and cytokine secretion.
  • A DR5 agonistic antibody (AD5-10) also triggered inflammatory cytokine release.

Conclusions:

  • TRAIL receptors (DR4 and DR5) play a significant role in initiating inflammatory responses.
  • NF-kappaB activation is a critical mediator of TRAIL receptor-induced inflammation.
  • Crosstalk between apoptosis and inflammatory signaling pathways is crucial for DR4/DR5-mediated cytokine release.

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