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.
Highlights
Vascular endothelial cell growth factor (VEGF) is a multifaceted cytokine [1]
We found that the presence of a Tumor necrosis factor superfamily 15 (TNFSF15) neutralizing antibody, 4-3H [25], in the culture media prevented TNFSF15 inhibition of VEGF production at mRNA and protein levels (Figure 1F, 1G); the amount of secreted VEGF in the cell culture media declined under the experimental conditions (Figure 1H)
We show in this study that TNFSF15, a cytokine produced largely by endothelial cells and a potent inhibitor of endothelial cell proliferation, is able to down-regulate VEGF gene expression
Summary
Vascular endothelial cell growth factor (VEGF) is a multifaceted cytokine [1]. TNFSF15 can induce proliferating endothelial cells to undergo apoptosis [22] and inhibit angiogenesis [23]. The expression of the TNFSF15 gene in endothelial cells is often found at high levels in mature vasculature in normal tissues, it diminishes in angiogenic vasculatures such as in cancers [26,27,28] and wound tissues [29]. A number of cytokines, noticeably VEGF, can effectively suppress TNFSF15 production [26] These experimental data indicate that VEGF and TNFSF15 may act as a pair of counter-balancing factors in the maintenance of vascular integrity and regulation of neovascularization
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
