Tumor Necrosis Factor Superfamily-15 Inhibits VEGF Gene Expression via microRNA-29b

Tumor necrosis factor superfamily-15 (TNFSF15; VEGI), a cytokine largely produced by endothelial cells, specifically inhibits endothelial cell proliferation and endothelial progenitor cell differentiation. Vascular endothelial growth factor (VEGF) plays a pivotal role in the regulation of blood vessel growth and function. We report here that TNFSF15 is able to downregulate VEGF gene expression. Treatment of mouse endothelial cell line bEnd3 with TNFSF15 results in a decrease of VEGF at both mRNA and protein levels, and at the same time an increase of microRNA-29b (miR-29b). Overexpression of miR-29b in bEnd3 leads to suppressed VEGF expression. Elimination of miR-29b gives rise to increased VEGF expression. Blocking TNFSF15-activated signals by using either siRNA against death domain-containing receptor-3 (DR3; TNFRSF25), which is the receptor of TNFSF15 on endothelial cells, or a neutralizing antibody 4-3H against TNFSF15 leads to a suppression of TNFSF15-induced miR-29b expression. We have determined the intracellular signaling pathways resulting from TNFSF15-stimulation and leading to miR-29b upregulation. These findings are consistent with the view that TNFSF15 is a critical regulator of VEGF activities.