Expression of Soluble Vascular Endothelial Growth Factor Receptor-1 in Human Monocyte-Derived Mature Dendritic Cells Contributes to Their Antiangiogenic Property

The soluble form of vascular endothelial growth factor receptor-1 (sVEGFR-1) is produced from endothelial cells by alternative splicing of VEGFR-1 mRNA, and can inhibit angiogenesis by blocking the biological effects of VEGF. In this study, we show the expression of a large amount of sVEGFR-1 in human monocyte-derived mature dendritic cells (mDCs). As compared with monocytes and immature DCs, mDCs generated by TNF-alpha or soluble CD40L with IFN-gamma, but not LPS or other stimuli, preferentially produce sVEGFR-1. We also detected the mRNA of sVEGFR-1 generated by alternative splicing of VEGFR-1 mRNA in mDCs induced by TNF-alpha. The production of sVEGFR-1 showed a distinct contrast to those of VEGF in each DC matured with various stimuli. The supernatant of DCs matured with TNF-alpha or soluble CD40L with IFN-gamma showed inhibition of the tube formation of HUVECs, which was neutralized by anti-VEGFR-1 Ab, indicating that sVEGFR-1 secreted from mDCs was biologically active. Interestingly, the supernatant of mDCs generated with LPS increased HUVEC capillary-like formation in vitro. The ratio of sVEGFR-1 to VEGF clearly reflected the net angiogenic property of mDCs. Administration of mDCs induced by TNF-alpha into the s.c. tumor of PC-14 cells implanted in SCID mice demonstrated the inhibition of tumor growth via reduction of the number of CD31-positive vessels, indicating their in vivo antiangiogenic potential. These results suggest that sVEGFR-1 produced by mDCs contribute to their antiangiogenic property, and the ratio of sVEGFR-1 to VEGF might be a useful tool for evaluating their ability to regulate angiogenesis mediated by VEGF.