Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2.
Dendritic cells (DCs) are the most potent antigen-presenting cells and play a central role in the host-antitumor immunity. Since it has been reported that vascular endothelial growth factor (VEGF) inhibits the functional maturation of immature-DCs and impairs DC differentiation, it is important to elucidate the mechanisms of VEGF-induced DC-dysfunction. To investigate the effects of VEGF against human mature DCs, we investigated how VEGF affects mature DCs with regards to phenotype, induction of apoptosis, IL-12(p70) production and the antigen-presenting function evaluated by allogeneic mixed leukocyte reaction (allo-MLR). We generated monocyte-derived DCs matured with lipopolysaccharide, OK-432 or pro-inflammatory cytokine cocktails. As a result, VEGF treatment did not alter the mature DCs with regard to phenotype, IL-12(p70) production and induction of apoptosis. As a novel and important finding, VEGF inhibited the ability of mature DCs to stimulate allogeneic T cells. Furthermore, this VEGF-induced DC dysfunction was mainly mediated by VEGF receptor-2 (VEGF R2). These observations were confirmed by the findings that the VEGF-induced DC dysfunction was recovered by anti-human VEGF neutralizing mAb or anti-human VEGF R2 blocking mAb, and that placenta growth factor (PlGF), VEGF R1-specific ligand, did not have any effect against mature DCs. Some modalities aiming at reversing mature-DC dysfunction induced by VEGF will be needed in order to induce the effective antitumor immunity.
Mimura
Kousaku
K
First Department of Surgery, University of Yamanashi, 1110 shimokato, Chuo-city, Yamanashi 409-3898, Japan.
Kono
Koji
K
Takahashi
Akihiro
A
Kawaguchi
Yoshihiko
Y
Fujii
Hideki
H
D017951:Antigen Presentation / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D007959:Lymphocyte Culture Test, Mixed; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology*
D042461:Vascular Endothelial Growth Factor A; D018664:Interleukin-12; D040301:Vascular Endothelial Growth Factor Receptor-2