TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis

J Clin Invest. 2008 Jan;118(1):111-23. doi: 10.1172/JCI29900.


Preclinical data support the potential of the death-signaling receptors for TRAIL as targets for cancer therapy. However, it is unclear whether these death-signaling receptors suppress the emergence and growth of malignant tumors in vivo. Herein we show that TNF-related apoptosis-inducing ligand receptor (TRAIL-R), the only proapoptotic death-signaling receptor for TRAIL in the mouse, suppresses inflammation and tumorigenesis. Loss of a single TRAIL-R allele on the lymphoma-prone Emu-myc genetic background significantly reduced median lymphoma-free survival. TRAIL-R-deficient lymphomas developed with equal frequency irrespective of mono- or biallelic loss of TRAIL-R, had increased metastatic potential, and showed apoptotic defects relative to WT littermates. In addition, TRAIL-R-/- mice showed decreased long-term survival following a sublethal dose of ionizing radiation. Histological evaluation of moribund irradiated TRAIL-R-/- animals showed hallmarks of bronchopneumonia as well as tumor formation with increased NF-kappaB p65 expression. TRAIL-R also suppressed diethylnitrosamine-induced (DEN-induced) hepatocarcinogenesis, as an increased number of large tumors with apoptotic defects developed in the livers of DEN-treated TRAIL-R-/- mice. Thus TRAIL-R may function as an inflammation and tumor suppressor in multiple tissues in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alkylating Agents / toxicity
  • Animals
  • Bronchitis / chemically induced
  • Bronchitis / genetics
  • Bronchitis / metabolism*
  • Bronchitis / pathology
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cell Transformation, Neoplastic / radiation effects
  • Chronic Disease
  • Diethylnitrosamine / toxicity
  • Humans
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Lymphoma / chemically induced
  • Lymphoma / genetics
  • Lymphoma / metabolism*
  • Lymphoma / pathology
  • Mice
  • Mice, Knockout
  • Pneumonia / chemically induced
  • Pneumonia / genetics
  • Pneumonia / metabolism*
  • Pneumonia / pathology
  • Radiation, Ionizing
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Whole-Body Irradiation / adverse effects


  • Alkylating Agents
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Tnfrsf10b protein, mouse
  • Transcription Factor RelA
  • Tumor Suppressor Proteins
  • Diethylnitrosamine