Abstract
Soluble tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), in contrast to membrane TWEAK and TNF, is only a weak activator of the classical NFκB pathway. We observed that soluble TWEAK was regularly more potent than TNF with respect to the induction of TNF receptor-associated factor 1 (TRAF1), a NFκB-controlled signaling protein involved in the regulation of inflammatory signaling pathways. TNF-induced TRAF1 expression was efficiently blocked by inhibition of the classical NFκB pathway using the IKK2 inhibitor, TPCA1. In contrast, in some cell lines, TWEAK-induced TRAF1 production was only partly inhibited by TPCA1. The NEDD8-activating enzyme inhibitor MLN4924, however, which inhibits classical and alternative NFκB signaling, blocked TNF- and TWEAK-induced TRAF1 expression. This suggests that TRAF1 induction by soluble TWEAK is based on the cooperative activity of the two NFκB signaling pathways. We have previously shown that oligomerization of soluble TWEAK results in ligand complexes with membrane TWEAK-like activity. Oligomerization of soluble TWEAK showed no effect on the dose response of TRAF1 induction, but potentiated the ability of soluble TWEAK to trigger production of the classical NFκB-regulated cytokine IL8. Transfectants expressing soluble TWEAK and membrane TWEAK showed similar induction of TRAF1 while only the membrane TWEAK expressing cells robustly stimulated IL8 production. These data indicate that soluble TWEAK may efficiently induce a distinct subset of the membrane TWEAK-targeted genes and argue again for a crucial role of classical NFκB pathway-independent signaling in TWEAK-induced TRAF1 expression. Other TWEAK targets, which can be equally well induced by soluble and membrane TWEAK, remain to be identified and the relevance of the ability of soluble TWEAK to induce such a distinct subset of membrane TWEAK-targeted genes for TWEAK biology will have to be clarified in future studies.
Highlights
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor (FGF)-inducible molecule-14 (Fn14), alternatively termed TweakR or TNFRSF12, form a phylogenetically well conserved ligand–receptor pair of the tumor necrosis factor (TNF) family
We observed that soluble TWEAK was regularly more potent than TNF with respect to the induction of TNF receptor-associated factor 1 (TRAF1), a NFκB-controlled signaling protein involved in the regulation of inflammatory signaling pathways
In the 2-h time window investigated, soluble TWEAK showed only delayed barely detectable IκBα phosphorylation and IκBα degradation was practically not evident (Figure 1A). This correlated with the fact that production of IL8, a cytokine that is dominantly regulated by the classical NFκB pathway, was much stronger induced by TNF than by soluble TWEAK (Figure 1B; Figure S1 in Supplementary Material)
Summary
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor (FGF)-inducible molecule-14 (Fn14), alternatively termed TweakR or TNFRSF12, form a phylogenetically well conserved ligand–receptor pair of the TNF family. Like most other members of the TNF receptor family, Fn14 activates proinflammatory signaling pathways with the help of adapter proteins of the TNF receptor-associated factor (TRAF) family, especially TRAF2 [5,6,7]. TRAF2 and the TRAF2-associated E3 ligases cellular inhibitor of apoptosis-1 (cIAP1) and cIAP2 are required by Fn14 for the activation of the classical NFκB pathway but are crucially involved in TWEAK-induced stimulation of MAP kinases [4, 8]. The question how the various Fn14-associated signaling pathways contribute, in which cell type, to the aforementioned biological effects of TWEAK and Fn14 is poorly understood. Two major mechanisms that contribute to the plasticity and variability of TWEAK/Fn14-mediated effects are based on the capability of Fn14 to adopt different states of activity and to modulate signaling by other members of the TNF receptor family
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