Akt is an endogenous inhibitor toward tumor necrosis factor-related apoptosis inducing ligand-mediated apoptosis in rheumatoid synovial cells

Biochem Biophys Res Commun. 2003 Dec 12;312(2):397-404. doi: 10.1016/j.bbrc.2003.10.141.

Abstract

Akt is known to be activated in the rheumatoid synovial tissues. We examined here functional role of Akt during tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis in rheumatoid synovial cells. Rheumatoid synovial cells in vitro were rapidly committed to apoptosis in response to TRAIL in mitochondria-dependent manner whereas Akt and extracellular signal-regulated kinase (ERK) were also phosphorylated. TRAIL-mediated apoptosis in synovial cells was significantly increased through inactivation of Akt by LY294002, however, that process was not so changed by adding ERK inhibitor, PD98059. Platelet-derived growth factor (PDGF) clearly phosphorylated both Akt and ERK in synovial cells, and PDGF pretreatment markedly suppressed TRAIL-mediated synovial cell apoptosis. The use of not PD98059 but LY294002 abrogated PDGF-mediated inhibitory effect toward TRAIL-induced apoptosis in synovial cells. The above protective effect of Akt was confirmed by the use of short interfering RNA (siRNA)-directed inhibition of Akt. Our data suggest that Akt is an endogenous inhibitor during TRAIL-mediated synovial cell apoptotic pathway, which may explain that synovial cells in situ of the rheumatoid synovial tissues are resistant toward apoptotic cell death in spite of death receptor expression.

MeSH terms

  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Arthritis, Rheumatoid / metabolism*
  • Cells, Cultured
  • Chromones / pharmacology
  • Enzyme Activation
  • Humans
  • Membrane Glycoproteins / metabolism*
  • Mitochondria / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Morpholines / pharmacology
  • Platelet-Derived Growth Factor / metabolism*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Synovial Membrane / drug effects
  • Synovial Membrane / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand
  • Teprotide
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • Chromones
  • Membrane Glycoproteins
  • Morpholines
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Teprotide
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases