Lymphotoxin beta receptor triggering induces activation of the nuclear factor kappaB transcription factor in some...

NFkappaB is a pleiotropic transcription factor capable of activating the expression of a great variety of genes critical for the immunoinflammatory response. Tumor necrosis factor alpha (TNFalpha) and lymphotoxin alpha (LTalpha, originally TNFbeta) are potent nuclear factor kappaB (NFkappaB) activators in various cell types. The LTalpha molecule, in addition to being secreted as a soluble trimer, can also form membrane-anchored heterotrimers with the LTbeta chain, another member of the TNF family. The LTalpha1beta2 heterotrimer binds a specific receptor, called the LTbeta receptor (LTbeta-R), which is also a member of the TNF receptor family. Here, we show that engagement of LTbeta-R with a soluble form of LTalpha1beta2 or with a specific anti-LTbeta-R agonistic monoclonal antibody CBE11 quickly induces activation of NFkappaB in HT-29 and WiDr human adenocarcinomas. LTbeta-R triggering activates NFkappaB and induces proliferation in WI-38 human lung fibroblasts. No NFkappaB activation is observed in human umbilical vein endothelial cells, correlating with the inability of LTbeta-R activation to induce expression of NFkappaB-dependent cell surface adhesion molecules. Thus, like several other members of the TNF receptor family, the LTbeta-R can activate NFkappaB following receptor ligation in some but not all LTbeta-R-positive cells.