Murdoch Craig, Tazzyman Simon, Webster Steve, Lewis Claire E
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.
J Immunol. 2007 Jun 1;178(11):7405-11. doi: 10.4049/jimmunol.178.11.7405.
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.
血管生成素1和2与内皮细胞上表达的Tie-2结合，调节血管稳定和血管生成。已证明Tie-2(+)单核细胞被募集到实验性肿瘤中，促进肿瘤血管生成。在本研究中，我们发现20%的CD14(+)人血单核细胞表达Tie-2，这些细胞共表达CD16（FcγRIII），且主要为CD34阴性。血管生成素2在恶性肿瘤和炎症组织中被内皮细胞上调，因此我们发现血管生成素2是人类Tie-2(+)单核细胞和巨噬细胞的趋化因子，这表明它可能有助于募集和调节它们在此类组织中的分布。还发现血管生成素2在体外能显著抑制单核细胞释放重要的促炎细胞因子肿瘤坏死因子-α。单核细胞渗出并分化为巨噬细胞后，许多会聚集在炎症和恶性组织的缺氧区域。已知血管生成素2在缺氧状态下会上调，我们发现单核细胞和巨噬细胞在暴露于缺氧环境时会上调Tie-2的表达。此外，缺氧增强了血管生成素2对单核细胞释放抗血管生成细胞因子白细胞介素-12的抑制作用。总之，我们的数据表明血管生成素2可能将Tie-2(+)单核细胞募集到肿瘤和炎症部位，调节它们释放重要细胞因子，并刺激它们表达促血管生成表型。
