Antioxidant c-FLIP Inhibits Fas Ligand-Induced NF-kappa B Activation in a Phosphatidylinositol 3-Kinase/Akt-Dependent Manner

作者：Iyer Anand Krishnan V^*; Azad Neelam; Talbot Siera; Stehlik Christian; Lu Bin; Wang Liying; Rojanasakul Yon

来源：The Journal of Immunology, 2011, 187(6): 3256-3266.

DOI：10.4049/jimmunol.1002915

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-kappa B and PI3K/Akt. However, it is not known whether cross-talk exists between NF-kappa 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-kappa B, Akt inhibits FasL-dependent NF-kappa B 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-kappa B upstream of the regulatory I kappa B kinase-gamma protein subunit in the NF-kappa B signaling pathway, and positive cross-talk exists between Akt and c-FLIP in the context of inhibition of FasL-induced NF-kappa B 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-kappa B activity. Taken together, our study reveals a novel link between NF-kappa B and PI3K/Akt and establishes c-FLIP as an important regulator of FasL-mediated cell death. The Journal of Immunology, 2011, 187: 3256-3266.

• 出版日期2011-9-15
• 单位西北大学