Vascular endothelial growth factor inhibits maturation of dendritic cells induced by lipopolysaccharide,but not by proinflammatory cytokines |
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Authors: | Akihiro?Takahashi Email author" target="_blank">Koji?KonoEmail author Fumiko?Ichihara Hidemitsu?Sugai Hideki?Fujii Yoshiro?Matsumoto |
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Institution: | (1) First Department of Surgery, University of Yamanashi, 1110 Shimokato, 409-3898 Tamaho, Yamanashi, Japan |
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Abstract: | Purpose: Dendritic cells (DCs) play an important role in the hosts immunosurveillance against cancer. It has been shown that the function of DCs is impaired and their population decreased in a cancer-bearing host. In the present study, we investigated the mechanism of down-regulation of DCs in a cancer-bearing host. Methods: We evaluated the relationship between DC infiltration and production of vascular endothelial growth factor (VEGF) in carcinoma tissue by immunohistochemistry. Furthermore, functional and phenotypical alterations of DCs were evaluated when monocyte-derived, mature DCs were treated with VEGF in vitro. Monocyte-derived DCs were generated in a culture of monocyte with interleukin 4 (IL-4) and granulocyte-macrophage colony-stimulating factor, and the maturation of DCs was induced by either lipopolysaccharide (LPS) or a proinflammatory cytokine cocktail: tumor-necrosis factor , prostaglandin E2, IL-6, and IL-1. Results: A significant inverse correlation was found between the density of DCs and the quantity of VEGF production in gastric carcinoma tissue (r=–0.39, p<0.05). In LPS-induced maturation, the ability of mature DCs to stimulate allogenic T cells and produce IL-12 (p70 heterodimer) was suppressed by the addition of VEGF in a dose-dependent manner. A lesser expression of costimulatory molecules (CD80 and CD86) was seen in DCs treated with exogenous VEGF than in DCs not treated with VEGF. The population of dead DCs (early and late apoptosis) treated with VEGF increased more than that without VEGF treatment, using the annexin V and propidium iodide evaluation in DCs matured by LPS. In contrast, in DCs matured by the proinflammatory cytokine cocktail, the down-regulation of costimulatory molecules and induction of DC apoptosis was not seen. Conclusions: These findings show that the inhibition of DC maturation by VEGF differs depending on the maturation status of the DCs.Abbreviations APC
antigen-presenting cells
- DC
dendritic cells
- ELISA
enzyme-linked immunosorbent assay
- FACS
fluorescence-activated cell sorter
- FCS
fetal calf serum
- FITC
fluorescein isothiocyanate
- GM-CSF
granulocyte-macrophage colony-stimulating factor
- HLA
human leukocyte antigen
- IL
interleukin
- LPS
lipopolysaccharide
- mAb
monoclonal antibody
- MHC
major histocompatibility complex
- PBS
phosphate-buffered saline
- PCNA
proliferative cell nuclear antigen
- PE
phycoerythrin
- PG
prostaglandin
- PI
propidium iodide
- TNF
tumor-necrosis factor
- VEGF
vascular endothelial growth factor
This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan. |
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Keywords: | Vascular endothelial growth factor Dendritic cells Apoptosis Gastric carcinoma Costimulatory molecule |
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