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Vascular endothelial growth factor inhibits maturation of dendritic cells induced by lipopolysaccharide, but not by proinflammatory cytokines

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Purpose: Dendritic cells (DCs) play an important role in the host’s 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 α, prostaglandin E2, IL-6, and IL-1β. 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.

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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

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Authors and Affiliations

  1. First Department of Surgery, University of Yamanashi, 1110 Shimokato, 409-3898, Tamaho, Yamanashi, Japan

    Akihiro Takahashi, Koji Kono, Fumiko Ichihara, Hidemitsu Sugai, Hideki Fujii & Yoshiro Matsumoto

Authors
  1. Akihiro Takahashi
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  2. Koji Kono
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  3. Fumiko Ichihara
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  4. Hidemitsu Sugai
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  5. Hideki Fujii
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  6. Yoshiro Matsumoto
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Correspondence to Koji Kono.

Additional information

This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

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Takahashi, A., Kono, K., Ichihara, F. et al. Vascular endothelial growth factor inhibits maturation of dendritic cells induced by lipopolysaccharide, but not by proinflammatory cytokines. Cancer Immunol Immunother 53, 543–550 (2004). https://doi.org/10.1007/s00262-003-0466-8

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  • DOI: https://doi.org/10.1007/s00262-003-0466-8

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