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First published online 18 December 2002
doi: 10.1242/jcs.00286

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VEGF expression in human macrophages is NF-B-dependent: studies using adenoviruses expressing the endogenous NF-B inhibitor IB and a kinase-defective form of the IB kinase 2

Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London W6 8LH, UK

^* Author for correspondence (e-mail: s.kiriakidis{at}ic.ac.uk)

Accepted 20 November 2002

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-B (NF-B) in monocytes, we investigated in this study whether VEGF production in macrophages, when stimulated with either LPS or CD40L, is NF-B-dependent. We used adenoviral constructs over-expressing either IB (AdvIB), the endogenous inhibitor of NF-B, or a kinase-defective mutant of IKK-2 (AdvIKK-2dn), an upstream activator of IB, 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 IB. In addition, we observed significant inhibition of the CD40L-induced VEGF production in macrophages following infection with AdvIB. 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-B activation. These results show for the first time that VEGF production in human macrophages is NF-B dependent. NF-B regulates many of the genes involved in immune and inflammatory responses, and our study adds the angiogenic cytokine VEGF to the list of NF-B-dependent cytokines.

Key words: VEGF, Macrophages, Angiogenesis, NF-B, Signalling, CD40 ligand

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