Expression of Tie-2 by human monocytes and their responses to angiopoietin-2.
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 (FcgammaRIII) 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-alpha, 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.
Murdoch
Craig
C
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.
Tazzyman
Simon
S
Webster
Steve
S
Lewis
Claire E
CE
D042702:Angiopoietin-2 / Q000502:physiology*; D000818:Animals; D015687:Cell Hypoxia / Q000276:immunology; D002462:Cell Membrane / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D006098:Granulocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D016131:Lymphocyte Subsets / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D042787:Receptor, TIE-2 / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
D042702:Angiopoietin-2; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D042787:Receptor, TIE-2