Multiple pathways of TWEAK-induced cell death

M. Nakayama, K. Ishidoh, N. Kayagaki, Y. Kojima, N. Yamaguchi, H. Nakano, E. Kominami, K. Okumura, H. Yagita

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146 Citations (Scopus)


TWEAK, a recently identified member of the TNF family, is expressed on IFN-γ-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.α and was inhibited by cycloheximide, the TWEAK-induced cell death in HSC3 cells or IFN-γ-treated HT-29 cells was not inhibited by anti-TNF-α 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-α-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.

Original languageEnglish
Pages (from-to)734-743
Number of pages10
JournalJournal of Immunology
Issue number2
Publication statusPublished - 2002 Jan 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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