title: The cathepsin B death pathway contributes to TNF plus IFN-gamma-mediated human endothelial injury.
abstract: Vascular endothelial cells are primary targets of cytokine-induced cell death leading to tissue injury. We previously reported that TNF in combination with LY294002, a PI3K inhibitor, activates caspase-independent cell death initiated by cathepsin B (Cat B) in HUVEC. We report that TNF in the presence of IFN-gamma activates Cat B as well as a caspase death pathway in both HUVEC and human dermal microvascular endothelial cells, but only activates caspase-mediated death in HeLa cells and human embryonic kidney (HEK)293 cells. Like LY294002, IFN-gamma triggers Cat B release from lysosomes in HUVEC. Cat B-triggered death involves mitochondria, indicated by release of cytochrome c, loss of mitochondrial membrane potential and inhibition of death by overexpressed Bcl-2. Cat B effects on mitochondria do not depend upon Bid cleavage. Unexpectedly, overexpression of a dominant negative mutated form of Fas-associated death domain protein (FADD), which blocks caspase activation by TNF, potentiates TNF activation of Cat B and cell death in HUVEC. Similarly, mutant Jurkat cells lacking FADD also show increased susceptibility to TNF-induced Cat B-dependent cell death. These observations suggest that the Cat B death pathway is cell type-specific and may contribute to cytokine-mediated human tissue injury and to the embryonic lethality of FADD gene disruption in mice.
authors: Department of Pathology and Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors: Jie Hui
authors: JH
authors: Li
authors: Jordan S
authors: JS
authors: Pober
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002401:Cathepsin B / Q000502:physiology*; D016923:Cell Death / Q000276:immunology; D002460:Cell Line; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D053200:Fas-Associated Death Domain Protein; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000502:physiology; D008833:Microcirculation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D002401:Cathepsin B