Fibroblast growth factor-inducible 14 mediates multiple pathways of TWEAK-induced cell death.
TWEAK, a TNF family member, is produced by IFN-gamma-stimulated monocytes and induces multiple pathways of cell death, including caspase-dependent apoptosis, cathepsin B-dependent necrosis, and endogenous TNF-alpha-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.
Nakayama
Masafumi
M
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Ishidoh
Kazumi
K
Kojima
Yuko
Y
Harada
Norihiro
N
Kominami
Eiki
E
Okumura
Ko
K
Yagita
Hideo
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000378:metabolism / Q000633:toxicity; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000502:physiology*; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002460:Cell Line / Q000378:metabolism / Q000648:ultrastructure; D000074049:Cytokine TWEAK; D005260:Female; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D019073:HT29 Cells / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D019169:Jurkat Cells / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D007940:Leukemia L5178 / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000074050:TWEAK Receptor; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D048069:Tumor Necrosis Factors
D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors