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Published online before print April 1, 2004

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(Journal of Leukocyte Biology. 2004;76:217-226.)
© 2004 by Society for Leukocyte Biology

Evidence for the involvement of SDF-1 and CXCR4 in the disruption of endothelial cell-branching morphogenesis and angiogenesis by TNF- and IFN-

Ombretta Salvucci^*,, Mark Basik, Lei Yao^*, Rossella Bianchi and Giovanna Tosato^*,1

^* Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland;
Department of Biomedical Sciences and Biotechnology, Division of Human Anatomy, University of Brescia, Italy; and
Translational Genomics Research Institute, Laboratory of Cancer Drug Development, Phoenix, Arizona

¹Correspondence: Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 12N226, MSC 1907, Bethesda, MD 20892. E-mail: tosatog{at}mail.nih.gov

Vigorous inflammatory responses are associated with tissue damage, particularly when toxic levels of inflammatory cytokines are produced. Despite proangiogenic factors being present early at sites of inflammation, vascular repair occurs toward the end of the inflammatory response, suggesting modulation of the proangiogenic response. Endogenous inhibitors of angiogenesis induced during acute inflammation are poorly characterized. Here, we looked for endothelial cell-derived modulators of angiogenesis that may account for delayed neovascularization during inflammation. Gene profiling of endothelial cells showed that the inflammatory cytokines tumor necrosis factor (TNF-) and interferon- (IFN-) selectively promote expression of the antiangiogenic molecules, IFN-inducible protein-10, monokine induced by IFN-, tryptophanyl-tRNA synthetase, and tissue inhibitor of metalmetalloproteinase-1, and inhibit expression of the proangiogenic molecules, platelet-endothelial cell adhesion molecule-1, vascular endothelial growth factor receptor-2, stromal cell-derived factor-1 (SDF-1), collagen type IV, endothelial cell growth factor-1, and carcinoembryonic antigen-related cell adhesion molecule-1. Reduced endothelial cell expression of SDF-1 protein by TNF- and IFN- disrupts extracellular matrix-dependent endothelial cell tube formation, an in vitro morphogenic process that recapitulates critical steps in angiogenesis. Replacement of SDF-1 onto the endothelial cell surface reconstitutes this morphogenic process. In vivo, TNF- and IFN- inhibit growth factor-induced angiogenesis and SDF-1 expression in endothelial cells. These results demonstrate that SDF-1/CXC chemokine receptor-4 constitutes a TNF-- and IFN--regulated signaling system that plays a critical role in mediating angiogenesis inhibition by these inflammatory cytokines.

Key Words: chemokine • cytokine • endothelium • inflammation

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