1. ¹Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Röntgenring 11, Würzburg 97070, Germany
2. ²Bundesinstitut für Risikobewertung, Thielallee 88-92, 14195 Berlin, Germany
3. ³Orthopädische Klinik, König Ludwig Haus, University Hospital Würzburg, Brettreichstrasse 11, Würzburg 97070, Germany
4. ⁴Klinik für Innere Medizin II, Klinikum Südstadt Rostock, Südring 81, 18059 Rostock, Germany

Correspondence: H Wajant, Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Roentgenring 11, Wuerzburg 97070, Germany. Tel: +49 931 201 71010; Fax: +49 931 201 71070; E-mail: harald.wajant@mail.uni-wuerzburg.de

Received 26 September 2008; Revised 20 May 2009; Accepted 20 May 2009; Published online 26 June 2009.

Abstract

Soluble TNF-like weak inducer of apoptosis (TWEAK) trimers induce, in a variety of cell lines, translocation of cytosolic tumor necrosis factor (TNF) receptor-associated factor-2 (TRAF2) to a triton X-100-insoluble compartment without changes in the total cellular TRAF2 content. TWEAK-induced TRAF2 translocation is paralleled by a strong increase in nuclear factor kappaB 2 (NFB2)/p100 processing to p52, indicating that TRAF2 redistribution is sufficient for activation of the alternative NFB pathway. In accordance with the crucial role of TRAF2 in proinflammatory, anti-apoptotic TNF receptor-1 (TNFR1) signaling, we observed that TWEAK-primed cells have a reduced capacity to activate the classical NFB pathway or JNK (cJun N-terminal kinase) in response to TNF. Furthermore, TWEAK-primed cells are sensitized for the TNFR1-mediated induction of apoptotic and necrotic cell death. Notably, the expression of the NFB-regulated, TRAF2-interacting TRAF1 protein can attenuate TWEAK-induced depletion of the triton X-100-soluble TRAF2 fraction and improve TNFR1-induced NFB signaling in TWEAK-primed cells. Taken together, we demonstrate that soluble TWEAK desensitizes cells for proinflammatory TNFR1 signaling and thus identify TWEAK as a modifier of TNF signaling.