Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells.
Vascular endothelial growth factor (VEGF), produced by almost all tumor cells, affects the ability of hemopoietic progenitor cells (HPC) to differentiate into functional dendritic cells (DC) during the early stages of their maturation. In this study we demonstrate specific binding of VEGF to HPC. This binding was efficiently competed by placenta growth factor (PIGF), a ligand reportedly specific for the Flt-1 receptor. The number of binding sites for VEGF decreased during DC maturation in vitro associated with decreased levels of mRNA for Flt-1. VEGF significantly inhibited nuclear factor-kappa B (NF-kappa B)-dependent activation of reporter gene transcription during the first 24 h in culture. The presence of VEGF significantly decreased the specific DNA binding of NF-kappa B as early as 30 min after induction with TNF-alpha. This was followed on days 7 to 10 by decreases in the mRNA for RelB and c-Rel, two subunits of NF-kappa B. Blockade of NF-kappa B activity in HPC at early stages of differentiation with an adenovirus expressing a dominant I kappa B inhibitor of NF-kappa B reproduced the pattern of effects observed with VEGF. Thus, NF-kappa B plays an important role in maturation of HPCs to DC, and VEGF activation of the Flt-1 receptor is able to block the activation of NF-kappa B in this system. Blockade of NF-kappa B activation in HPCs by tumor-derived factors may therefore be a mechanism by which tumor cells can directly down-modulate the ability of the immune system to generate effective antitumor immune responses.
Oyama
T
T
The Vanderbilt Cancer Center, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Ran
S
S
Ishida
T
T
Nadaf
S
S
Kerr
L
L
Carbone
D P
DP
Gabrilovich
D I
DI
D018952:Antigens, CD34 / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002474:Cell-Free System / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000502:physiology*; D005312:Fetal Blood; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D008222:Lymphokines / Q000378:metabolism / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D018952:Antigens, CD34; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D020672:I-kappa B Proteins; D008222:Lymphokines; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000072000:NF-KappaB Inhibitor alpha; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1