The cathepsin B death pathway contributes to TNF plus IFN-gamma-mediated human endothelial injury.
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.
Li
Jie Hui
JH
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.
Pober
Jordan S
JS
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*
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