Tie2 receptor tyrosine kinase, a major mediator of tumor necrosis factor α-induced angiogenesis in rheumatoid arthritis
Tie2 receptor tyrosine kinase, a major mediator of tumor necrosis factor α-induced angiogenesis in rheumatoid arthritis
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DOI：
10.1002/art.11213
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发表时间：
2003-09-01
影响因子：
--
通讯作者：
Lin, PC
中科院分区：
文献类型：
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作者：
DeBusk, LM;Chen, Y;Lin, PC
Objective.风湿性关节炎（RA）是一种炎症性疾病和血管生成性疾病。然而，促进RA血管生成的分子机制尚不清楚。我们的目的是研究内皮特异性受体酪氨酸激酶Tie2在炎症性关节炎血管生成中的作用。免疫组化和Western blot检测Tie2及其配体血管生成素1（Ang1）在人滑膜中的表达。建立了一种新的滑膜血管窗模型，以研究Tie2在体内血管生成中的作用。采用原代培养的内皮细胞和滑膜细胞研究肿瘤坏死因子α（TNF α）诱导的Tie2和Ang1表达。Tie2与病理性血管生成有关。我们观察到Tie2和Ang1在人RA滑膜中升高。使用一种新的胶原诱导的关节炎滑膜窗模型，我们证明了Tie2信号调节关节炎血管生成在体内。我们还在小鼠角膜测定中显示Tie2介导TNF α诱导的血管生成。此外，我们观察到TNF α可以通过多种方式调节Tie2的激活，这些方式可能涉及内皮细胞和滑膜细胞之间的相互作用。TNF α通过核因子κ B上调内皮细胞中的Tie 2，并上调滑膜细胞中的Ang1。提示内皮细胞和滑膜细胞间存在旁分泌调节血管生成的作用。这项研究表明，Tie2调节炎症滑膜中的血管生成。Tie2信号是一种重要的血管生成介质，其将促炎细胞因子TNF α与病理性血管生成联系起来。
Objective. Rheumatoid arthritis (RA) is an inflammatory disease and an angiogenic disease. However, the molecular mechanisms promoting angiogenesis in RA are not clearly identified. Our objective was to study the role of an endothelium-specific receptor tyrosine kinase, Tie2, in angiogenesis of inflammatory arthritis.Methods. Expression of Tie2 and its ligand, angiopoietin 1 (Ang1), in human synovium was examined by immunohistochemistry and Western blot. A novel synovium vascular window model was established to study the role of Tie2 in angiogenesis in vivo. Primary cultured endothelial cells and synoviocytes were used to study tumor necrosis factor alpha (TNFalpha)-induced Tie2 and Ang1 expression.Results. Tie2 was implicated in pathologic angiogenesis. We observed that Tie2 and Ang1 were elevated in human RA synovium. Using a novel collagen-induce arthritis synovial window model, we demonstrated that Tie2 signaling regulated arthritis angiogenesis in vivo. We also showed that Tie2 mediated TNFalpha-induced angiogenesis in a mouse cornea assay. In addition, we observed that TNFalpha can regulate Tie2 activation in multiple ways that may involve interactions between endothelial cells and synoviocytes. TNFalpha up-regulates Tie2 in endothelial cells through nuclear factor kappaB, and it up-regulates Ang1 in synoviocytes. These findings suggest paracrine regulation of angiogenesis between endothelial cells and synoviocytes.Conclusion. This study demonstrates that Tie2 regulates angiogenesis in inflammatory synovium. Tie2 signaling is an important angiogenic mediator that links the proinflammatory cytokine TNFalpha to pathologic angiogenesis.