Cancer Immunology, Immunotherapy

, Volume 53, Issue 6, pp 543–550

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

  • Akihiro Takahashi
  • Koji Kono
  • Fumiko Ichihara
  • Hidemitsu Sugai
  • Hideki Fujii
  • Yoshiro Matsumoto
Original Article

DOI: 10.1007/s00262-003-0466-8

Cite this article as:
Takahashi, A., Kono, K., Ichihara, F. et al. Cancer Immunol Immunother (2004) 53: 543. doi:10.1007/s00262-003-0466-8

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.

Keywords

Vascular endothelial growth factorDendritic cellsApoptosisGastric carcinomaCostimulatory molecule

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

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Akihiro Takahashi
    • 1
  • Koji Kono
    • 1
  • Fumiko Ichihara
    • 1
  • Hidemitsu Sugai
    • 1
  • Hideki Fujii
    • 1
  • Yoshiro Matsumoto
    • 1
  1. 1.First Department of SurgeryUniversity of YamanashiTamahoJapan