Fibroblast growth factor-inducible 14 mediates multiple pathways of TWEAK-induced cell death

Masafumi Nakayama, Kazumi Ishidoh, Yuko Kojima, Norihiro Harada, Eiki Kominami, Ko Okumura, Hideo Yagita

Research output: Contribution to journalArticlepeer-review

115 Citations (Scopus)

Abstract

TWEAK, a TNF family member, is produced by IFN-γ-stimulated monocytes and induces multiple pathways of cell death, including caspase-dependent apoptosis, cathepsin B-dependent necrosis, and endogenous TNF-α-mediated cell death, in a cell type-specific manner. However, the TWEAK receptor(s) that mediates these multiple death pathways remains to be identified. Recently, fibroblast growth factor-inducible 14 (Fn14) has been identified to be a TWEAK receptor, which was responsible for TWEAK-induced proliferation of endothelial cells and angiogenesis. Because Fn14 lacks the cytoplasmic death domain, it remains unclear whether Fn14 can also mediate the TWEAK-induced cell death. In this study, we demonstrated that TWEAK could induce apoptotic cell death in Fn14 transfectants. A pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, rather sensitized the Fn14 transfectants to TWEAK-induced cell death by necrosis via reactive oxygen intermediates and cathepsin B-dependent pathway. By using newly generated agonistic anti-Fn14 mabs, we also observed that Fn14 is constitutively expressed on the cell surface of all TWEAK-sensitive tumor cell lines, and can transmit the multiple death signals. Moreover, an anti-Fn14 mAb that blocks TWEAK-Fn14 interaction could totally abrogate TWEAK binding and TWEAK-induced cell death in all TWEAK-sensitive tumor cell lines. These results revealed that the multiple pathways of TWEAK-induced cell death are solely mediated by Fn14.

Original languageEnglish
Pages (from-to)341-348
Number of pages8
JournalJournal of Immunology
Volume170
Issue number1
DOIs
Publication statusPublished - 2003 Jan 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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