Unfractionated heparin suppresses lipopolysaccharide-induced monocyte chemoattractant protein-1 expression in human microvascular endothelial cells by blocking Kruppel-like factor 5 and nuclear factor-κB pathway
Unfractionated heparin suppresses lipopolysaccharide-induced monocyte chemoattractant protein-1 expression in human microvascular endothelial cells by blocking Kruppel-like factor 5 and nuclear factor-κB pathway
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DOI：
10.1016/j.imbio.2014.06.005
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发表时间：
2014-10-01
期刊：
影响因子：
2.8
通讯作者：
Ma, Xiaochun
中科院分区：
文献类型：
--
作者：
Li, Xu;Li, Xin;Ma, Xiaochun
未分级肝素（UFH）和低分子量肝素（LMWH）除了具有抗凝血活性外，还具有多种生物学特性，如抗炎作用，可能影响败血症。趋化因子对于促进循环白细胞向感染部位的运动至关重要，并参与败血症的发病机制。本研究的目的是探讨UFH对脂多糖（LPS）诱导的人肺微血管内皮细胞（hpmes）趋化因子产生的影响及其潜在机制。在LPS （10 μ g/ml）刺激前15分钟，分别用UFH （0.1 U/ml和1 U/ml）预处理hpmes。细胞在不同实验条件下培养2 ~ 6 h进行分析。UFH显著降低lps诱导的白细胞介素(IL)-8和单核细胞趋化蛋白-1 (MCP-1) mRNA和蛋白的表达。UFH还能减弱培养上清液中这些趋化因子的分泌。此外，如预期的那样，UFH阻断了lps刺激的hpmes上清对单核细胞迁移的趋化活性。UFH抑制lps诱导的Kruppel-like factor 5 (KLF-5) mRNA和蛋白水平。同时，UFH减少核因子(NF)- κ B核易位。重要的是，转染靶向KLF-5的siRNA可降低NF-kappa B的激活和趋化因子的表达。这些结果表明，干扰KLF-5介导的NF-kappa B激活可能有助于UFH抑制趋化因子和单核细胞迁移在lps刺激的hpmes中的作用。(C) 2014 Elsevier GmbH版权所有。
Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH), apart from anticoagulant activities, contain a variety of biological properties such as anti-inflammatory actions possibly affecting sepsis. Chemokines are vital for promoting the movement of circulating leukocytes to the site of infection and are involved in the pathogenesis of sepsis. The purpose of this study was to investigate the effects and potential mechanisms of UFH on lipopolysaccharide (LPS)-induced chemokine production in human pulmonary microvascular endothelial cells (HPMECs). HPMECs were pretreated with UFH (0.1 U/ml and 1 U/ml), 15 min prior to stimulation with LPS (10 mu g/ml). Cells were cultured under various experimental conditions for 2 hand 6 h for analysis. UFH markedly decreased LPS-induced interleukin (IL)-8 and monocyte chemoattractant protein-1 (MCP-1) mRNA and protein expression in HPMECs. UFH also attenuated the secretion of these chemokines in culture supernatants. In addition, UFH blocked the chemotactic activities of LPS-stimulated HPMECs supernatants on monocytes migration as expected. UFH inhibited LPS-induced Kruppel-like factor 5 (KLF-5) mRNA and protein levels. Concurrently, UFH reduced nuclear factor (NF)-kappa B nuclear translocation. Importantly, transfection with siRNA targeting KLF-5 reduced NF-kappa B activation and chemokines expression. These results demonstrate that interfering with KLF-5 mediated NF-kappa B activation might contribute to the inhibitory effects of chemokines and monocytes migration by UFH in LPS-stimulated HPMECs. (C) 2014 Elsevier GmbH. All rights reserved.