title: The involvement of TNF-alpha-related apoptosis-inducing ligand in the enhanced cytotoxicity of IFN-beta-stimulated human dendritic cells to tumor cells.
abstract: TNF-alpha-related apoptosis-inducing ligand (TRAIL) is characterized by its preferential induction of apoptosis of tumor cells but not normal cells. Dendritic cells (DCs), besides their role as APCs, now have been demonstrated to exert cytotoxicity or cytostasis on some tumor cells. Here, we report that both human CD34(+) stem cell-derived DCs (CD34DCs) and human CD14(+) monocyte-derived DCs (MoDCs) express TRAIL and exhibit cytotoxicity to some types of tumor cells partially through TRAIL. Moderate expression of TRAIL appeared on CD34DCs from the 8th day of culture and was also seen on freshly isolated monocytes. The level of TRAIL expression remained constant until DC maturation. TRAIL expression on immature CD34DCs or MoDCs was greatly up-regulated after IFN-beta stimulation. Moreover, IFN-beta could strikingly enhance the ability of CD34DCs or MoDCs to kill TRAIL-sensitive tumor cells, but LPS did not have such an effect. The up-regulation of TRAIL on IFN-beta-stimulated DCs partially contributed to the increased cytotoxicity of DCS: Pretreatment of TRAIL-sensitive tumor cells with caspase-3 inhibitor could significantly increase their resistance to the cytotoxicity of IFN-beta-stimulated DCS: In contrast, NF-kappaB inhibitor could significantly increase the sensitivity of tumor cells to the killing by nonstimulated or LPS-stimulated DCS: Our studies demonstrate that IFN-beta-stimulated DCs are functionally cytotoxic. Thus, an innate mechanism of DC-mediated antitumor immunity might exist in vivo in which DCs act as effectors to directly kill tumor cells partially via TRAIL. Subsequently, DCs act as APCs involved in the uptake, processing, and presentation of apoptotic tumor Ags to cross-prime CD8(+) CTL cells.
authors: Department of Immunology, Second Military Medical University, Shanghei, People's Republic of China.
authors: S
authors: S
authors: Liu
authors: Y
authors: Y
authors: Yu
authors: M
authors: M
authors: Zhang
authors: W
authors: W
authors: Wang
authors: X
authors: X
authors: Cao
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000502:physiology; D018952:Antigens, CD34 / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D006131:Growth Inhibitors / Q000502:physiology; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D019169:Jurkat Cells; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*; D020298:U937 Cells; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D018952:Antigens, CD34; D051017:Apoptosis Regulatory Proteins; D006131:Growth Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases