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Expression of Tie-2 by Human Monocytes and Their Responses to Angiopoietin-2¹

Tumor Targeting Group, Academic Unit of Pathology, Division of Genomic Medicine, The Sir Henry Wellcome Laboratories for Medical Research, University of Sheffield Medical School, Sheffield, United Kingdom

Angiopoietins 1 and 2 bind to Tie-2 expressed on endothelial cells and regulate vessel stabilization and angiogenesis. Tie-2⁺ monocytes have been shown to be recruited to experimental tumors where they promote tumor angiogenesis. In this study, we show that 20% of CD14⁺ human blood monocytes express Tie-2, and that these cells coexpress CD16 (FcRIII) and are predominantly CD34 negative. Ang-2 is up-regulated by endothelial cells in malignant tumors and inflamed tissues, so our finding that Ang-2 is a chemoattractant for human Tie-2⁺ monocytes and macrophages, suggests that it may help to recruit and regulate their distribution in such tissues. Ang-2 was also found to markedly inhibit release of the important proinflammatory cytokine, TNF-, by monocytes in vitro. Following extravasation of monocytes, and their differentiation into macrophages, many accumulate in the hypoxic areas of inflamed and malignant tissues. Ang-2 is known to be up-regulated by hypoxia and we show that monocytes and macrophages up-regulate Tie-2 when exposed to hypoxia. Furthermore, hypoxia augmented the inhibitory effect of Ang-2 on the release of the anti-angiogenic cytokine, IL-12 by monocytes. In sum, our data indicate that Ang-2 may recruit Tie-2⁺ monocytes to tumors and sites of inflammation, modulate their release of important cytokines and stimulate them to express a proangiogenic phenotype.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by research funding from the Biotechnology and Biological Sciences Research Council and Yorkshire Cancer Research.

² Current address: Department of Oral and Maxillofacial Surgery, University of Sheffield School of Clinical Dentistry, Sheffield, United Kingdom

³ Address correspondence and reprint requests to Dr. Claire E. Lewis, Tumor Targeting Group, Academic Unit of Pathology, Division of Genomic Medicine, The Sir Henry Wellcome Laboratories for Medical Research, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, U.K. E-mail address: claire.lewis{at}sheffield.ac.uk

⁴ Abbreviations used in this paper: Ang, angiopoietin; VEGF, vascular endothelial growth factor; MDM, monocyte-derived macrophage; HuDMEC, human dermal microvascular endothelial cell.

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