title: TRAIL promotes caspase-dependent pro-inflammatory responses via PKCδ activation by vascular smooth muscle cells.
abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is best known for its selective cytotoxicity against transformed tumor cells. Most non-transformed primary cells and several cancer cell lines are not only resistant to death receptor-induced apoptosis, but also subject to inflammatory responses in a nuclear factor-κB (NF-κB)-dependent manner. Although the involvement of TRAIL in a variety of vascular disorders has been proposed, the exact molecular mechanisms are unclear. Here, we aimed to delineate the role of TRAIL in inflammatory vascular response. We also sought possible molecular mechanisms to identify potential targets for the prevention and treatment of post-angioplastic restenosis and atherosclerosis. Treatment with TRAIL increased the expression of intercellular adhesion molecule-1 by primary human vascular smooth muscle cells via protein kinase C (PKC)δ and NF-κB activation. Following detailed analysis using various PKCδ mutants, we determined that PKCδ activation was mediated by caspase-dependent proteolysis. The protective role of PKCδ was further confirmed in post-traumatic vascular remodeling in vivo. We propose that the TRAIL/TRAIL receptor system has a critical role in the pathogenesis of inflammatory vascular disorders by transducing pro-inflammatory signals via caspase-mediated PKCδ cleavage and subsequent NF-κB activation.
authors: Department of Bio and Brain Engineering, KAIST, Yuseong-gu, Daejeon, Korea.
authors: S
authors: S
authors: Song
authors: K
authors: K
authors: Choi
authors: S-W
authors: SW
authors: Ryu
authors: S W
authors: SW
authors: Kang
authors: C
authors: C
authors: Choi
mesh_terms: D017209:Apoptosis / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism* / Q000494:pharmacology; D020298:U937 Cells
chemical_list: D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D018799:Intercellular Adhesion Molecule-1; D051745:Protein Kinase C-delta; D020169:Caspases