Multiple pathways of TWEAK-induced cell death

J Immunol. 2002 Jan 15;168(2):734-43. doi: 10.4049/jimmunol.168.2.734.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Antigens, CD / physiology
  • Apoptosis / drug effects
  • Apoptosis / immunology*
  • Apoptosis Regulatory Proteins
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology*
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cathepsin B / physiology
  • Cell Death / drug effects
  • Cell Death / immunology
  • Cytokine TWEAK
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • HT29 Cells
  • Humans
  • Interferon-gamma / physiology
  • Jurkat Cells
  • Leukemia L5178 / metabolism
  • Ligands
  • Mice
  • Necrosis
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • Receptors, Tumor Necrosis Factor / 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


  • 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