Antioxidant c-FLIP inhibits Fas ligand-induced NF-kB activation in a phosphatidylinositol 3-kinase/Akt-dependent manner

Details

• Personal Author:
  Azad N ; Iyer AKV ; Lu B ; Rojanasakul Y ; Stehlik C ; Talbot S ; Wang L
• Description:
  Fas ligand (FasL) belongs to the TNF family of death ligands, and its binding to the FasR leads to activation of several downstream signaling pathways and proteins, including NF-kB and PI3K/Akt. However, it is not known whether cross-talk exists between NF-?B and PI3K/Akt in the context of FasL signaling. We demonstrate using both human renal epithelial 293T cells and Jurkat T-lymphocyte cells that although FasL activates both Akt and NF-kB, Akt inhibits FasL-dependent NF-kB activity in a reactive oxygen species-dependent manner. Cellular FLICE-inhibitory protein (c-FLIP), an antioxidant and an important component of the death-inducing signaling complex, also represses NF-?B upstream of the regulatory IkB kinase-y protein subunit in the NF-kB signaling pathway, and positive cross-talk exists between Akt and c-FLIP in the context of inhibition of FasL-induced NF-kB activity. The presence of two death effector domains of c-FLIP and S-nitrosylation of its caspase-like domain were found to be important for mediating c-FLIP-dependent downregulation of NF-kB activity. Taken together, our study reveals a novel link between NF-kB and PI3K/Akt and establishes c-FLIP as an important regulator of FasL-mediated cell death. [Description provided by NIOSH]
• Subjects:
  Antioxidants Cells, Cultured Immune System Occupational Health Safety
• Keywords:
  Antioxidation Cell-biology Cell-cultures Cell-damage Cell-function Humans Immune-reaction Immunochemistry Immunology Proteins
• ISSN:
  0022-1767
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Illinois ; Massachusetts ; OSHA Region 1 ; OSHA Region 3 ; OSHA Region 5 ; Virginia ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  187
• Issue:
  6
• NIOSHTIC Number:
  nn:20039755
• Citation:
  J Immunol 2011 Sep; 187(6):3256-3266
• Contact Point Address:
  Dr. Anand Krishnan V. Iyer, Department of Pharmaceutical Sciences, Hampton University, Hampton, VA 23668
• Email:
  anand.iyer@hamptonu.edu
• Federal Fiscal Year:
  2011
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  The Journal of Immunology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:698d377986d08a72969f1169ea9df6a6c92a0f6a7af8c487ea644e95f7c4ee40d7f670a18d0e3b16cef8a44da639974260b44a5a341de923a8125f51a9093052
• Download URL:
  https://stacks.cdc.gov/view/cdc/192873/cdc_192873_DS1.pdf
• File Type:
  [PDF - 1.17 MB ]