Membrane Lymphotoxin-Alpha(2)Beta Is A Novel Tumor Necrosis Factor (Tnf) Receptor 2 (Tnfr2) Agonist

In the early 1990s, it has been described that LT alpha and LT beta form LT alpha (2)beta and LT alpha beta (2) heterotrimers, which bind to TNFR1 and LT beta R, respectively. Afterwards, the LT alpha beta (2)-LT beta R system has been intensively studied while the LT alpha (2)beta -TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LT alpha (2)beta -TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LT alpha. Here, we show that LT alpha (2)beta interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LT alpha (2)beta (memLT alpha (2)beta), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LT alpha (2)beta is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LT alpha.