TNF-like weak inducer of apoptosis inhibits proinflammatory TNF receptor-1 signaling

Wicovsky, A.; Salzmann, S.; Roos, C.; Ehrenschwender, M.; Rosenthal, T.; Siegmund, D.; Henkler, F.; Gohlke, F.; Kneitz, C.; Wajant, H.

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 (NF?B2)/p100 processing to p52, indicating that TRAF2 redistribution is sufficient for activation of the alternative NF?B 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 NF?B 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 NF?B-regulated, TRAF2-interacting TRAF1 protein can attenuate TWEAK-induced depletion of the triton X-100-soluble TRAF2 fraction and improve TNFR1-induced NF?B 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.



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Wicovsky, A. / Salzmann, S. / Roos, C. / et al: TNF-like weak inducer of apoptosis inhibits proinflammatory TNF receptor-1 signaling. 2009.


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