INVITRO AND INVIVO ACTIVATION OF ENDOTHELIAL-CELLS BY COLONY-STIMULATING FACTORS
INVITRO AND INVIVO ACTIVATION OF ENDOTHELIAL-CELLS BY COLONY-STIMULATING FACTORS
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DOI：
10.1172/jci115107
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发表时间：
1991-03-01
影响因子：
15.9
通讯作者：
MANTOVANI, A
中科院分区：
文献类型：
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作者：
BUSSOLINO, F;ZICHE, M;MANTOVANI, A
本研究旨在鉴定造血生长因子、粒细胞集落刺激因子(G-CSF)和粒细胞巨噬细胞集落刺激因子(GM-CSF)对培养内皮细胞激活的一系列功能，并将它们与这些细胞上激活的原型细胞因子所激活的功能进行比较。此外，还获得了体外效应与体内相关性的迹象。G-CSF和GM-CSF可诱导内皮细胞增殖和迁移。相反，与适当的参考细胞因子(IL-1和肿瘤坏死因子)不同，G-CSF和GM-CSF不调节与止血相关的内皮细胞功能：血栓(产生促凝血剂活性和血小板激活因子)、炎症(白细胞黏附分子-1的表达和血小板激活因子的产生)和辅助功能(MHC的II类抗原的表达)。其他集落刺激因子(IL-3和巨噬细胞集落刺激因子)对所有测试的功能均无效。与碱性成纤维细胞生长因子(BFGF)相比，G-CSF和GM-CSF诱导的内皮细胞最大增殖率较低，而迁移幅度相同。G-CSF和GM-CSF促进机械损伤内皮单分子层的修复。暴露于这两种细胞因子可引起形态改变和细胞骨架重组，符合迁移性表型。为了探讨这些细胞因子对内皮细胞的体外作用在体内的相关性，我们研究了人G-CSF在兔角膜中的血管生成活性。G-CSF，而不是热灭活的分子，具有明确的血管生成活性，没有任何炎症反应的迹象。G-CSF活性低于bFGF。然而，非血管生成剂量的碱性成纤维细胞生长因子与G-CSF联合使用时，血管生成反应比单独使用细胞因子时要高。因此，G-CSF和GM-CSF诱导内皮细胞表达与血管生成相关的激活/分化程序(包括增殖和迁移)。
This study was designed to identify the set of functions activated in cultured endothelial cells by the hematopoietic growth factors, granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage-colony-stimulating factor (GM-CSF), and to compare them with those elicited by prototypic cytokines active on these cells. Moreover, indications as to the in vivo relevance of in vitro effects were obtained. G-CSF and GM-CSF induced endothelial cells to proliferate and migrate. In contrast, unlike appropriate reference cytokines (IL-1 and tumor necrosis factor, IFN-gamma), G-CSF and GM-CSF did not modulate endothelial cell functions related to hemostasis-thrombosis (production of procoagulant activity and of platelet activating factor), inflammation (expression of leukocyte adhesion molecule-1 and production of platelet activating factor), and accessory function (expression of class II antigens of MHC). Other colony-stimulating factors (IL-3 and macrophage-colony-stimulating factor) were inactive on all functions tested. In comparison to basic fibroblast growth factor (bFGF), G-CSF and GM-CSF induced lower maximal proliferation of endothelial cells, whereas migration was of the same order of magnitude. G-CSF and GM-CSF stimulated repair of mechanically wounded endothelial monolayers. Exposure to both cytokines induced shape changes and cytoskeletal reorganization consistent with a migratory phenotype. To explore the in vivo relevance of the in vitro effects of these cytokines on endothelium, we studied the angiogenic activity of human G-CSF in the rabbit cornea. G-CSF, but not the heat-inactivated molecule, had definite angiogenic activity, without any sign of inflammatory reactions. G-CSF was less active than bFGF. However, the combination of a nonangiogenic dose of bFGF with G-CSF resulted in an angiogenic response higher than that elicited by either individual cytokines. Thus, G-CSF and GM-CSF induce endothelial cells to express an activation/differentiation program (including proliferation and migration) related to angiogenesis.