title: TWEAK can induce cell death via endogenous TNF and TNF receptor 1.
abstract: TWEAK is a recently cloned novel member of the TNF ligand family. Here we show that soluble TWEAK is sufficient to induce apoptosis in Kym-1 cells within 18 h. TWEAK-induced apoptosis is indirect and is mediated by the interaction of endogenous TNF and TNF receptor (TNFR)1, as each TNFR1-Fc, neutralizing TNF-specific antibodies and TNFR1-specific Fab fragments efficiently antagonize cell death induction. In addition to this indirect mode of action, co-stimulation of Kym-1 cells with TWEAK enhances TNFR1-mediated cell death induction. In contrast to TNF, TWEAK does only modestly activate NF-kappaB or c-jun N-terminal kinase (JNK) in Kym-1 cells. Although TWEAK binding to Kym-1 cells is easily detectable by flow cytometric analysis, we found neither evidence for expression of the recently identified TWEAK receptor Apo3/TRAMP/wsl/DR3/LARD, nor indications for direct interactions of TWEAK with TNFR. Together, these characteristics of TWEAK-induced signaling in Kym-1 cells argue for the existence of an additional, still undefined non-death domain-containing TWEAK receptor in Kym-1 cells.
authors.affiliation: Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Schneider
authors.forename: R
authors.initials: R
authors.lastname: Schwenzer
authors.forename: E
authors.initials: E
authors.lastname: Haas
authors.forename: F
authors.initials: F
authors.lastname: Mühlenbeck
authors.forename: G
authors.initials: G
authors.lastname: Schubert
authors.forename: P
authors.initials: P
authors.lastname: Scheurich
authors.forename: J
authors.initials: J
authors.lastname: Tschopp
authors.forename: H
authors.initials: H
authors.lastname: Wajant
mesh_terms: D015703:Antigens, CD / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002460:Cell Line; D000074049:Cytokine TWEAK; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D048069:Tumor Necrosis Factors
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D000074049:Cytokine TWEAK; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; C506033:TNFRSF25 protein, human; C109743:TNFSF12 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors