TRAIL induces apoptosis and inflammatory gene expression in human endothelial cells.
Human TRAIL can efficiently kill tumor cells in vitro and kill human tumor xenografts in mice with little effect on normal mouse cells or tissues. The effects of TRAIL on normal human tissues have not been described. In this study, we report that endothelial cells (EC), isolated from human umbilical veins or human dermal microvessels, express death domain-containing TRAIL-R1 and -R2. Incubation with TRAIL for 15 h causes approximately 30% of cultured EC to die, as assessed by propidium iodide uptake. Death is apoptotic, as assessed by Annexin V staining, 4',6'-diamidino-2-phenylindole staining, and DNA fragment ELISA. EC death is increased by cotreatment with cycloheximide but significantly reduced by caspase inhibitors or transduced dominant-negative Fas-associated death domain protein. In surviving cells, TRAIL activates NF-kappaB, induces expression of E-selectin, ICAM-1, and IL-8, and promotes adhesion of leukocytes. Injection of TRAIL into human skin xenografts promotes focal EC injury accompanied by limited neutrophil infiltration. These data suggest that TRAIL is an inducer of tissue injury in humans, an outcome that may influence antitumor therapy with TRAIL.
Li
Jie Hui
JH
Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
Kirkiles-Smith
Nancy C
NC
McNiff
Jennifer M
JM
Pober
Jordan S
JS
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000473:pathology* / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D007271:Injections, Intradermal; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D020556:Neutrophil Infiltration / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D016038:Skin Transplantation / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014183:Transplantation, Heterologous / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha