VEGI, a new member of the TNF family activates Nuclear Factor-kappa B and c-Jun N-terminal kinase and modulates cell growth

Recently a new member of the human tumor necrosis factor (TNF) family named as VEGI was reported. However, very little is known about the biological a ctivities displayed by this cytokine. In this report, we show that in myelo id cells VEGI activated the transcription factor kappa B (NF-kappa B) as de termined by the electrophoretic mobility shift assay, induced degradation o f I kappa B alpha, and nuclear translocation of p65 subunit of NF-kappa B. VEGI also activated NF-kappa B-dependent reporter gene expression. In addit ion, VEGI activated c-Jun N-terminal kinase. When examined for growth modul atory effects, VEGI inhibited the proliferation of breast carcinoma (MCF-7) , epithelial (HeLa), and myeloid (U-937 and ML-1a) tumor cells; and activat ed caspase-3 leading to PARP cleavage. VEGI-induced cytotoxicity was potent iated by inhibitors of protein synthesis. VEGI also induced proliferation o f normal human foreskin fibroblast cells. The activity of VEGI could neithe r be neutralized by antibodies against TNF, nor could it compete with TNF b inding, indicating that the activity of VEGI is not due to TNF and it binds to a distinct receptor. These results suggest that VEGI, a new member of t he TNF family, has a signaling pathway similar to TNF and is most likely a multifunctional cytokine.