title: Multiple pathways of TWEAK-induced cell death.
abstract: TWEAK, a recently identified member of the TNF family, is expressed on IFN-gamma-stimulated monocytes and induces cell death in certain tumor cell lines. In this study, we characterized the TWEAK-induced cell death in several tumor cell lines that exhibited distinct features. Although the TWEAK-induced cell death in Kym-1 cells was indirectly mediated by TNF-alpha and was inhibited by cycloheximide, the TWEAK-induced cell death in HSC3 cells or IFN-gamma-treated HT-29 cells was not inhibited by anti-TNF-alpha mAb or cycloheximide, suggesting a direct triggering of cell death via TWEAK receptor in the latter cell lines. The TWEAK-induced apoptosis in HSC3 cells and IFN-gamma-treated HT-29 cells was associated with caspase-8 and caspase-3 activation. Although a pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, inhibited the TWEAK-induced cell death in HSC3 cells, it rather sensitized HT-29 cells to TWEAK-induced cell death by necrosis. This necrosis was abrogated by lysosomal proteinase inhibitors, particularly a cathepsin B inhibitor, [L-3-trans-(propylcarbamoyl)oxirane-2-carbonyl]-L-isoleucyl-L-proline methyl ester. During the process of TWEAK-induced necrosis, cathepsin B was released from lysosome to cytosol. Although DR3 has been reported to be a receptor for TWEAK, all TWEAK-sensitive tumor cell lines used in this study did not express DR3 at either protein or mRNA level, but did bind CD8-TWEAK specifically. These results indicated that TWEAK could induce multiple pathways of cell death, including both caspase-dependent apoptosis and cathepsin B-dependent necrosis, in a cell type-specific manner via TWEAK receptor(s) distinct from DR3.
authors.affiliation: Department of Immunology, Allergy Research Center, Division of Pathology, Central Laboratory of Medical Sciences, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakayama
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ishidoh
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kayagaki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kojima
authors.forename: Noriko
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Nakano
authors.forename: Eiki
authors.initials: E
authors.lastname: Kominami
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002401:Cathepsin B / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D000074049:Cytokine TWEAK; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D019073:HT29 Cells; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D019169:Jurkat Cells; D007940:Leukemia L5178 / Q000378:metabolism; D008024:Ligands; D051379:Mice; D009336:Necrosis; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000502:physiology; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000276:immunology*; D000074050:TWEAK Receptor; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D048069:Tumor Necrosis Factors
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D000074049:Cytokine TWEAK; D008024:Ligands; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; C506033:TNFRSF25 protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C506034:Tnfrsf25 protein, mouse; C491645:Tnfsf12 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D007371:Interferon-gamma; D020169:Caspases; D002401:Cathepsin B