Bi-directional signaling of TRAIL on cell activation and apoptosis

• Main Authors: Ai-Hsiang Chou, 周愛湘
• Other Authors: Ping-Ning Hsu
• Format: Others
• Language: en_US
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/96263737412289971031

博士 === 國立臺灣大學 === 免疫學研究所 === 92 === TNF-related apoptosis-inducing ligand (TRAIL, also called Apo2L), a novel member of TNF superfamily, induces apoptosis in transformed cell lines of diverse origin but not in most of the primary cells. TRAIL is expressed in most of the cells, and the expression is upregulated in activated T cells. Five receptors for TRAIL have been identified, and there is complex interplay between TRAIL and TRAIL receptors in vivo. Role in tumor killing has been suggested based on in vitro study, however, the actual biological function of TRAIL/TRAIL receptor is still not clear. In order to study the biological role of TRAIL, we first explored the possibility of reverse signaling of TRAIL in T cells. We demonstrated that cross-linking of TRAIL by plate-bound rTRAIL receptor, death receptor 4-Fc (DR4-Fc) fusion protein, enhanced T cell proliferation in conjunction with immobilized suboptimal anti-CD3 Ab stimulation. Engagement of TRAIL on anti-CD3 activated T cells also increased IFNg production and this effect could be blocked by SB203580, a p38 mitogen activated protein kinase (MAPK)-specific inhibitor. These results indicated the occurrence of reverse signaling through TRAIL on T cell and signal the augmentation of IFNg secretion via a p38-dependent pathway. Our results provide another example of reverse signaling by a member of TNF superfamily, suggesting that bi-directional signaling is a general phenomenon among TNF superfamily. These results also shed light on biological function of TRAIL. To further explore the regulatory mechanism of TRAIL-mediated apoptosis, we studied TRAIL death receptor apoptosis signaling pathway and its regulation. We investigated the modulation of apoptosis signaling by hepatitis C virus (HCV) core protein to delineate the regulation of TRAIL-mediated apoptosis. The core protein of HCV is a viral nucleocapsid, which has been shown to affect various intracellular events including cell proliferation and apoptosis. We demonstrated that HCV core protein sensitizes human HCC cell line, Huh7, conferred sensitivity to TRAIL- but not FasL-mediated apoptosis. The induction of TRAIL sensitivity by HCV core protein was due to facilitating activation of caspase-8 and its downstream pathway, and enhancing Bid processing, breakdown of mitochondrial transmembrane potential as well as cytochrome c release. Therefore, the HCV core protein-induced TRAIL- mediated apoptosis via enhancing the activation of caspase-8 downstream pathway to convey death signal to mitochondria, leading to activation of mitochondrial signaling pathway and breaking apoptosis resistance. Taken together, our results indicate a bi-directional signaling of TRAIL. Engagement of TRAIL with TRAIL receptor induces costimulation of T cells. On the other hand, engagement of TRAIL death receptor with TRAIL could also induce cell death via transducing apoptotic signal which could be modulated by pathogens or microorganisms. Our results add a new dimension of biological function of TRAIL and TRAIL receptors in immune mediated diseases.