Abstract The proliferation and migration of endothelial cells are vascular events of inflammation, a process which can also potentiate the effects of promigratory factors. With the aim of investigating possible modifications in the activity of erythropoietin (Epo) in an inflammatory environment, we found that Epo at a non-promigratory concentration was capable of stimulating EA.hy926 endothelial cell migration when TNF-α was present. VCAM-1 and ICAM-1 expression, as well as adhesion of monocytic THP-1 cells to endothelial layers were also increased. Structurally modified Epo (carbamylation or N-homocysteinylation) did not exhibit these effects. The sensitizing effect of TNF-α on Epo activity was mediated by the Epo receptor. Inhibition assays targeting the PI3K/mTOR/NF-κB pathway, shared by Epo and TNF-α, show a cross-talk between both cytokines. As observed in assays using antioxidants, cell migration elicited by TNF-α + Epo depended on TNF-α-generated reactive oxygen species (ROS). ROS-mediated inactivation of protein tyrosine phosphatase 1B (PTP1B), involved in Epo signaling termination, could explain the synergistic effect of these cytokines. Our results suggest that ROS generated by inflammation inactivate PTP1B, causing the Epo signal to last longer. This mechanism, along with the cross-talk between both cytokines, could explain the sensitizing action of TNF-α on the migratory effect of Epo.

中文翻译：

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蛋白酪氨酸磷酸酶 1B (PTP1B) 在增加内皮细胞对促红细胞生成素在炎症环境中的迁移作用的敏感性中的作用

摘要 内皮细胞的增殖和迁移是炎症的血管事件，这一过程也可以增强迁移因子的作用。为了研究炎症环境中促红细胞生成素 (Epo) 活性的可能改变，我们发现当 TNF-α 存在时，非迁移浓度的 Epo 能够刺激 EA.hy926 内皮细胞迁移。VCAM-1 和 ICAM-1 表达以及单核细胞 THP-1 细胞与内皮层的粘附也增加。结构修饰的 Epo（氨基甲酰化或 N-高半胱氨酸化）没有表现出这些影响。TNF-α 对 Epo 活性的增敏作用是由 Epo 受体介导的。针对 Epo 和 TNF-α 共有的 PI3K/mTOR/NF-κB 通路的抑制测定显示两种细胞因子之间存在串扰。正如在使用抗氧化剂的测定中所观察到的，由 TNF-α + Epo 引起的细胞迁移取决于 TNF-α 产生的活性氧 (ROS)。ROS 介导的蛋白酪氨酸磷酸酶 1B (PTP1B) 失活，参与 Epo 信号终止，可以解释这些细胞因子的协同作用。我们的结果表明炎症产生的 ROS 使 PTP1B 失活，导致 Epo 信号持续更长时间。这种机制，连同两种细胞因子之间的串扰，可以解释 TNF-α 对 Epo 迁移效应的敏化作用。可以解释这些细胞因子的协同作用。我们的结果表明炎症产生的 ROS 使 PTP1B 失活，导致 Epo 信号持续更长时间。这种机制，连同两种细胞因子之间的串扰，可以解释 TNF-α 对 Epo 迁移效应的敏化作用。可以解释这些细胞因子的协同作用。我们的结果表明炎症产生的 ROS 使 PTP1B 失活，导致 Epo 信号持续更长时间。这种机制，连同两种细胞因子之间的串扰，可以解释 TNF-α 对 Epo 迁移效应的敏化作用。