Cargando…
TNF Receptor-Associated Factor 1 is a Major Target of Soluble TWEAK
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...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927163/ https://www.ncbi.nlm.nih.gov/pubmed/24600451 http://dx.doi.org/10.3389/fimmu.2014.00063 |
_version_ | 1782304076578422784 |
---|---|
author | Carmona Arana, José Antonio Seher, Axel Neumann, Manfred Lang, Isabell Siegmund, Daniela Wajant, Harald |
author_facet | Carmona Arana, José Antonio Seher, Axel Neumann, Manfred Lang, Isabell Siegmund, Daniela Wajant, Harald |
author_sort | Carmona Arana, José Antonio |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3927163 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-39271632014-03-05 TNF Receptor-Associated Factor 1 is a Major Target of Soluble TWEAK Carmona Arana, José Antonio Seher, Axel Neumann, Manfred Lang, Isabell Siegmund, Daniela Wajant, Harald Front Immunol Immunology 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. Frontiers Media S.A. 2014-02-18 /pmc/articles/PMC3927163/ /pubmed/24600451 http://dx.doi.org/10.3389/fimmu.2014.00063 Text en Copyright © 2014 Carmona Arana, Seher, Neumann, Lang, Siegmund and Wajant. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Carmona Arana, José Antonio Seher, Axel Neumann, Manfred Lang, Isabell Siegmund, Daniela Wajant, Harald TNF Receptor-Associated Factor 1 is a Major Target of Soluble TWEAK |
title | TNF Receptor-Associated Factor 1 is a Major Target of Soluble TWEAK |
title_full | TNF Receptor-Associated Factor 1 is a Major Target of Soluble TWEAK |
title_fullStr | TNF Receptor-Associated Factor 1 is a Major Target of Soluble TWEAK |
title_full_unstemmed | TNF Receptor-Associated Factor 1 is a Major Target of Soluble TWEAK |
title_short | TNF Receptor-Associated Factor 1 is a Major Target of Soluble TWEAK |
title_sort | tnf receptor-associated factor 1 is a major target of soluble tweak |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927163/ https://www.ncbi.nlm.nih.gov/pubmed/24600451 http://dx.doi.org/10.3389/fimmu.2014.00063 |
work_keys_str_mv | AT carmonaaranajoseantonio tnfreceptorassociatedfactor1isamajortargetofsolubletweak AT seheraxel tnfreceptorassociatedfactor1isamajortargetofsolubletweak AT neumannmanfred tnfreceptorassociatedfactor1isamajortargetofsolubletweak AT langisabell tnfreceptorassociatedfactor1isamajortargetofsolubletweak AT siegmunddaniela tnfreceptorassociatedfactor1isamajortargetofsolubletweak AT wajantharald tnfreceptorassociatedfactor1isamajortargetofsolubletweak |