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TNF Receptor-Associated Factor 1 is a Major Target of Soluble TWEAK

Please always quote using this URN: urn:nbn:de:bvb:20-opus-120620
  • 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. InSoluble 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.show moreshow less

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Metadaten
Author: José Antonio Carmona Arana, Axel Seher, Manfred Neumann, Isabell Lang, Daniela Siegmund, Harald Wajant
URN:urn:nbn:de:bvb:20-opus-120620
Document Type:Journal article
Faculties:Medizinische Fakultät / Klinik und Poliklinik für Mund-, Kiefer- und Plastische Gesichtschirurgie
Medizinische Fakultät / Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II)
Language:English
Parent Title (English):Frontiers in Immunology
ISSN:1664-3224
Year of Completion:2014
Volume:5
Issue:63
Source:Frontiers in Immunology 5:63. doi: 10.3389/fimmu.2014.00063
DOI:https://doi.org/10.3389/fimmu.2014.00063
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=24600451
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:CD40; NFκB; RAF1; TNF; TWEAK
Release Date:2016/02/12
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung