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: Masafumi Nakayama, Kazumi Ishidoh, Nobuhiko Kayagaki, Yuko Kojima, Noriko Yamaguchi, Hiroyasu Nakano, Eiki Kominami, Ko Okumura, Hideo Yagita
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 168 Issue 2 Pg. 734-43 (Jan 15 2002) ISSN: 0022-1767 [Print] United States
• PMID: 11777967 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Antigens, CD
• Apoptosis Regulatory Proteins
• Carrier Proteins
• Caspase Inhibitors
• Cytokine TWEAK
• Ligands
• Receptors, Tumor Necrosis Factor
• Receptors, Tumor Necrosis Factor, Member 25
• Receptors, Tumor Necrosis Factor, Type I
• TNFRSF25 protein, human
• TNFSF12 protein, human
• TWEAK Receptor
• Tnfrsf25 protein, mouse
• Tnfsf12 protein, mouse
• Tumor Necrosis Factor-alpha
• Tumor Necrosis Factors
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• Interferon-gamma
• Caspases
• Cathepsin B

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Antigens, CD (physiology)
• Apoptosis (drug effects, immunology)
• Apoptosis Regulatory Proteins
• Carrier Proteins (metabolism, physiology)
• Caspase Inhibitors
• Caspases (metabolism)
• Cathepsin B (physiology)
• Cell Death (drug effects, immunology)
• Cytokine TWEAK
• Enzyme Activation (drug effects, immunology)
• HT29 Cells
• Humans
• Interferon-gamma (physiology)
• Jurkat Cells
• Leukemia L5178 (metabolism)
• Ligands
• Mice
• Necrosis
• Receptors, Tumor Necrosis Factor (biosynthesis, physiology)
• Receptors, Tumor Necrosis Factor, Member 25
• Receptors, Tumor Necrosis Factor, Type I
• Signal Transduction (immunology)
• TWEAK Receptor
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (physiology)
• Tumor Necrosis Factors