TNFSF15 suppresses VEGF production in endothelial cells by stimulating miR-29b expression via activation of JNK-GATA3 signals

// Kun Zhang 1,2 , Hong-Xing Cai 1,2 , Shan Gao 1,2 , Gui-Li Yang 1,2 , Hui-Ting Deng 1,2 , Guo-Ce Xu 1,2 , Jihong Han 2,3 , Qiang-Zhe Zhang 1,2 and Lu-Yuan Li 1,2 1 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China 2 Collaborative Innovation Center for Biotherapy, Nankai University, West China Hospital, Sichuan University, Chengdu, China 3 College of Life Sciences, Nankai University, Tianjin, China Correspondence to: Lu-Yuan Li, email: // Qiang-Zhe Zhang, email: // Keywords : tumor necrosis factor superfamily 15; vascular endothelial cell growth factor; microRNA; GATA3; angiogenesis Received : April 30, 2016 Accepted : August 25, 2016 Published : August 29, 2016 Abstract Vascular endothelial cell growth factor (VEGF) plays a pivotal role in promoting neovascularization. VEGF gene expression in vascular endothelial cells in normal tissues is maintained at low levels but becomes highly up-regulated in a variety of disease settings including cancers. Tumor necrosis factor superfamily 15 (TNFSF15; VEGI; TL1A) is an anti-angiogenic cytokine prominently produced by endothelial cells in a normal vasculature. We report here that VEGF production in mouse endothelial cell line bEnd.3 can be inhibited by TNFSF15 via microRNA-29b (miR-29b) that targets the 3’-UTR of VEGF transcript. Blocking TNFSF15 activity by using either siRNA against the TNFSF15 receptor known as death domain-containing receptor-3 (DR3; TNFRSF25), or a neutralizing antibody 4-3H against TNFSF15, led to inhibition of miR-29b expression and reinvigoration of VEGF production. In addition, we found that TNFSF15 activated the JNK signaling pathway as well as the transcription factor GATA3, resulting in enhanced miR-29b production. Treatment of the cells either with SP600125, an inhibitor of JNK, or with JNK siRNA, led to eradication of TNFSF15-induced GATA3 expression. Moreover, GATA3 siRNA suppressed TNFSF15-induced miR-29b expression. These findings suggest that VEGF gene expression can be suppressed by TNFSF15-stimulated activation of the JNK-GATA3 signaling pathway which gives rise to up-regulation of miR-29b.