Journal
BIOLOGICAL & PHARMACEUTICAL BULLETIN
Volume 40, Issue 4, Pages 504-509Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/bpb.b16-00938
Keywords
Roundabout4; nuclear factor kappaB; tumor necrosis factor alpha; endothelial cell; inflammation
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Funding
- JSPS KAKENHI [JP 26293014]
- Japan Agency for Medical Research and Development, AMED
- Grants-in-Aid for Scientific Research [26293014] Funding Source: KAKEN
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Roundabout4 (Robo4) is an endothelial cell-specific receptor that regulates vascular stability. Recently, Robo4 has been shown to regulate vascular permeability in inflammation. However, the mechanisms regulating the Robo4 gene in the context of inflammation are poorly understood. In this study, we found that intravenous injection of tumor necrosis factor (TNF) alpha increased Robo4 expression in mouse organs. In vitro analyses showed that TNF alpha increased Robo4 expression in human primary endothelial cells, but not in cells pretreated with a nuclear factor (NF)-kappa B inhibitor. Reporter assays using wild-type and mutant Robo4 promoters indicated that TNF alpha activated the Robo4 promoter and that both the -2753 and -2220 NF-kappa B motifs were essential for this activation. Electrophoretic mobility shift assays demonstrated that the NF-kappa B p65-p50 heterodimer bound to these motifs. These findings were further supported by chromatin immunoprecipitation assays in endothelial cells. Taken together, these results indicated that TNFa induced Robo4 expression by facilitating NF-kappa B p65-p50 heterodimer binding to the -2753 and -2220 motifs in the Robo4 promoter in endothelial cells in the context of inflammation.
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