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Vascular endothelial growth factor (VEGF) is the most endothelial cell-specific angiogenic factor characterised to date, and it is produced by a variety of cell types. In macrophages, VEGF has been shown to be upregulated by the inflammatory mediator lipopolysaccharide (LPS) and by engagement of CD40 by CD40 ligand (CD40L). Because LPS and CD40L activate nuclear factor-kappaB (NF-kappaB) in monocytes, we investigated in this study whether VEGF production in macrophages, when stimulated with either LPS or CD40L, is NF-kappaB-dependent. We used adenoviral constructs over-expressing either IkappaBalpha (AdvIkappaBalpha), the endogenous inhibitor of NF-kappaB, or a kinase-defective mutant of IKK-2 (AdvIKK-2dn), an upstream activator of IkappaBalpha, to infect normal human monocyte-derived macrophages. We observed that LPS-induced production of VEGF in human macrophages was almost completely inhibited (>90%) following adenoviral transfer of IkappaBalpha. In addition, we observed significant inhibition of the CD40L-induced VEGF production in macrophages following infection with AdvIkappaBalpha. Expression of IKK-2dn in macrophages decreased VEGF production in response to LPS or CD40L by approximately 50%, suggesting that in addition to IKK-2, other kinases might be involved in NF-kappaB activation. These results show for the first time that VEGF production in human macrophages is NF-kappaB dependent. NF-kappaB regulates many of the genes involved in immune and inflammatory responses, and our study adds the angiogenic cytokine VEGF to the list of NF-kappaB-dependent cytokines.

Type

Journal article

Journal

J Cell Sci

Publication Date

15/02/2003

Volume

116

Pages

665 - 674

Keywords

Adenoviridae, Antibodies, CD40 Ligand, Cells, Cultured, Down-Regulation, Endothelial Growth Factors, Gene Expression Regulation, Genetic Vectors, Humans, I-kappa B Kinase, I-kappa B Proteins, Inflammation, Intercellular Signaling Peptides and Proteins, Lipopolysaccharides, Lymphokines, MAP Kinase Signaling System, Macrophages, Mutation, NF-KappaB Inhibitor alpha, NF-kappa B, Neovascularization, Pathologic, Protein-Serine-Threonine Kinases, Tumor Necrosis Factor-alpha, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors