IFN-gamma/JAK/STAT pathway-induced inhibition of DR4 and DR5 expression on endothelial cells is cancelled by cycloheximide-sensitive mechanism: novel finding of cycloheximide-regulating death receptor expression

Int J Mol Med. 2005 May;15(5):833-9.


The pathway of interferon gamma (IFN-gamma-induced suppression in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated endothelial cell apoptosis was investigated. rTRAIL triggered apoptosis of human umbilical vein endothelial cells (HUVECs) in a type II cell death manner. IFN-gamma pretreatment significantly suppressed the expression of death receptor 4 (DR4) and DR5 on HUVECs, and inhibited apoptosis in response to TRAIL. IFN-gamma rapidly phosphorylated signal transducers and activators of transcription 1 (STAT1) and STAT6 but did not enhance phosphorylation of STAT3, Akt and extracellular signal-regulated kinase (ERK) and nuclear translocation of NF-kappaB p65. Janus kinase (JAK)-induced phosphorylation of STAT1/6 appeared to be crucial since chemical inhibition of JAK abolished phosphorylation of STAT1/6, down-regulation of DR4/DR5 expression and IFN-gamma-induced inhibition of TRAIL-mediated apoptosis. IFN-gamma/JAK/STAT-induced suppression was regulated by cycloheximide (CHX)-sensitive mechanism since the use of CHX mimicked the action of chemical inhibition of JAK in regard to DR4/DR5 expression as well as TRAIL-mediated endothelial cell apoptosis. We have not yet clarified precise mechanism, however, the present data provide a novel finding that IFN-gamma/JAK/STAT pathway elicits inhibition of TRAIL-mediated endothelial cell apoptosis through CHX-sensitive suppression of DR4/DR5.

MeSH terms

  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Cells, Cultured
  • Cycloheximide / pharmacology*
  • DNA-Binding Proteins / physiology*
  • Endothelial Cells / metabolism*
  • Endothelium, Vascular / cytology
  • Humans
  • Interferon-gamma / pharmacology
  • Interferon-gamma / physiology*
  • Membrane Glycoproteins / metabolism
  • NF-kappa B / metabolism
  • Phosphorylation
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors*
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • STAT6 Transcription Factor
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand
  • Trans-Activators / physiology*
  • Tumor Necrosis Factor-alpha / metabolism
  • Umbilical Veins / cytology


  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Cycloheximide