TY  - JOUR
A1  - Kucka, Kirstin
A1  - Lang, Isabell
A1  - Zhang, Tengyu
A1  - Siegmund, Daniela
A1  - Medler, Juliane
A1  - Wajant, Harald
T1  - Membrane lymphotoxin-α\(_2\)β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist
JF  - Cell Death & Disease
N2  - In the early 1990s, it has been described that LTα and LTβ form LTα\(_2\)β and LTαβ\(_2\) heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ\(_2\)–LTβR system has been intensively studied while the LTα\(_2\)β–TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα\(_2\)β–TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα\(_2\)β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα\(_2\)β (memLTα\(_2\)β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα\(_2\)β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.
KW  - cytokines
KW  - signal transduction
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260077
VL  - 12
IS  - 4
ER  - 
TY  - JOUR
A1  - Carmona Arana, José Antonio
A1  - Seher, Axel
A1  - Neumann, Manfred
A1  - Lang, Isabell
A1  - Siegmund, Daniela
A1  - Wajant, Harald
T1  - TNF Receptor-Associated Factor 1 is a Major Target of Soluble TWEAK
JF  - Frontiers in Immunology
N2  - 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.
KW  - RAF1
KW  - TWEAK
KW  - TNF
KW  - NFκB
KW  - CD40
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120620
SN  - 1664-3224
VL  - 5
IS  - 63
ER  -