Wang Yinfang, Li Jinping, Huang Yitong, Dai Xiuqin, Liu Youbin, Liu Zongjun, Wang Ying, Wang Nanping, Zhang Peng
Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Cardiovascular Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
FASEB J. 2017 May;31(5):2026-2036. doi: 10.1096/fj.201600988RR. Epub 2017 Feb 3.
Angiogenesis and inflammation are regarded as important factors in the pathogenesis of chronic inflammation, cancer, and wound healing. Recent studies have supported prior evidence that common signaling pathways are involved in angiogenesis and inflammatory responses; however, key factors controlling both processes remain unclear. Although tripartite motif-containing (TRIM)-28 is known to have an immunosuppressive role in immune cells, its expression level and role in endothelial cells (ECs) are still unclear. In this study, we investigated the role of TRIM28 in inflammatory responses and angiogenic activity of ECs for the first time. We showed that TRIM28 is the most abundant TRIM family member and is localized in nuclei of ECs. Small interfering RNA-mediated knockdown of TRIM28 strikingly suppressed expression of TNF receptor (TNFR)-1 and -2, decreased TNF-α-induced phosphorylation of IKKα/β and IκBα and degradation of IκBα and nuclear translocation of p65, and suppressed basal level and TNF-α-induced expression of chemokines and adhesion molecules, including VCAM-1, IL-6, ICAM-1, E-selectin, and monocyte chemoattractant protein (MCP)-1. Unexpectedly, IL-8 was potentiated by TRIM28 knockdown in ECs in an NF-κB-inducing kinase-dependent manner. Meanwhile, knockdown of TRIM28 inhibited expression of VEGF receptor 2 and suppressed VEGF-induced proliferation and tube formation by ECs. Finally, knockdown of TRIM28 suppressed recruitment of ECs in a murine synthetic basement membrane model. In summary, we found that TRIM28 acts as a central factor in controlling endothelial inflammatory responses and angiogenic activities by retaining expression of TNFR-1 and -2 and VEGF receptor 2 in ECs.-Wang, Y., Li, J., Huang Y., Dai, X., Liu, Y., Liu, Z., Wang, Y., Wang, N., Zhang, P. Tripartite motif-containing 28 bridges endothelial inflammation and angiogenic activity by retaining expression of TNFR1 and -2 and VEGFR2 in endothelial cells.
血管生成和炎症被视为慢性炎症、癌症及伤口愈合发病机制中的重要因素。近期研究支持了先前的证据，即常见信号通路参与血管生成和炎症反应；然而，控制这两个过程的关键因素仍不清楚。尽管已知含三联基序（TRIM）-28在免疫细胞中具有免疫抑制作用，但其在内皮细胞（ECs）中的表达水平和作用仍不明确。在本研究中，我们首次探究了TRIM28在ECs炎症反应和血管生成活性中的作用。我们发现TRIM28是TRIM家族中表达最丰富的成员，且定位于ECs的细胞核中。小干扰RNA介导的TRIM28敲低显著抑制了肿瘤坏死因子受体（TNFR）-1和-2的表达，降低了肿瘤坏死因子-α诱导的IKKα/β和IκBα磷酸化以及IκBα降解和p65核转位，并抑制了趋化因子和黏附分子（包括血管细胞黏附分子-1、白细胞介素-6、细胞间黏附分子-1、E-选择素和单核细胞趋化蛋白-1）的基础水平及肿瘤坏死因子-α诱导的表达。出乎意料的是，在ECs中，TRIM28敲低以一种依赖核因子-κB诱导激酶的方式增强了白细胞介素-8的表达。同时，TRIM28敲低抑制了血管内皮生长因子受体2的表达，并抑制了血管内皮生长因子诱导的ECs增殖和管腔形成。最后，在小鼠合成基底膜模型中，TRIM28敲低抑制了ECs的募集。总之，我们发现TRIM28通过维持ECs中TNFR-1和-2以及血管内皮生长因子受体2的表达，在控制内皮炎症反应和血管生成活性中起核心作用。-王，Y.，李，J.，黄，Y.，戴，X.，刘，Y.，刘，Z.，王，Y.，王，N.，张，P.含三联基序的28通过维持内皮细胞中TNFR1和-2以及VEGFR2的表达连接内皮炎症和血管生成活性
