TNF-like weak inducer of apoptosis inhibits proinflammatory TNF receptor-1 signaling.
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 (NFkappaB2)/p100 processing to p52, indicating that TRAF2 redistribution is sufficient for activation of the alternative NFkappaB 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 NFkappaB 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 NFkappaB-regulated, TRAF2-interacting TRAF1 protein can attenuate TWEAK-induced depletion of the triton X-100-soluble TRAF2 fraction and improve TNFR1-induced NFkappaB 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.
Wicovsky
A
A
Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Röntgenring 11, Würzburg 97070, Germany.
Salzmann
S
S
Roos
C
C
Ehrenschwender
M
M
Rosenthal
T
T
Siegmund
D
D
Henkler
F
F
Gohlke
F
F
Kneitz
C
C
Wajant
H
H
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D000074049:Cytokine TWEAK; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017830:Octoxynol / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction; D047990:TNF Receptor-Associated Factor 1 / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000494:pharmacology*
D000074049:Cytokine TWEAK; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors; D017830:Octoxynol; D048031:JNK Mitogen-Activated Protein Kinases