Abstract：
The plant alkaloid homoharringtonine (HHT) is a Food and Drug Administration (FDA)-approved drug for the treatment of hematologic malignancies. In addition to its well-established antitumor activity, accumulating evidence attributes anti-inflammatory effects to HHT, which have mainly been studied in leukocytes to date. However, a potential influence of HHT on inflammatory activation processes in endothelial cells, which are a key feature of inflammation and a prerequisite for the leukocyte-endothelial cell interaction and leukocyte extravasation, remains poorly understood. In this study, the anti-inflammatory potential of HHT and its derivative harringtonine (HT) on the TNF-induced leukocyte-endothelial cell interaction was assessed, and the underlying mechanistic basis of these effects was elucidated. HHT affected inflammation in vivo in a murine peritonitis model by reducing leukocyte infiltration and proinflammatory cytokine expression as well as ameliorating abdominal pain behavior. In vitro, HT and HHT impaired the leukocyte-endothelial cell interaction by decreasing the expression of the endothelial cell adhesion molecules intracellular adhesion molecule -1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). This effect was mediated by a bipartite mechanism. While HHT did not affect the prominent TNF-induced pro-inflammatory NF-ĸB signaling cascade, the compound downregulated the VCAM1 mRNA expression in an IRF-1-dependent manner and diminished active ICAM1 mRNA translation as determined by polysome profiling. This study highlights HHT as an anti-inflammatory compound that efficiently hampers the leukocyte-endothelial cell interaction by targeting endothelial activation processes.
摘要：
植物生物碱高三尖杉酯碱（HHT）是食品和药物管理局（FDA）批准的用于治疗血液恶性肿瘤的药物。除了其公认的抗肿瘤活性，越来越多的证据将抗炎作用归因于HHT，迄今为止主要在白细胞中进行了研究。然而,HHT对内皮细胞炎症激活过程的潜在影响，这是炎症的关键特征，也是白细胞-内皮细胞相互作用和白细胞外渗的先决条件，仍然知之甚少。在这项研究中,评估了HHT及其衍生物三尖杉酯碱（HT）对TNF诱导的白细胞-内皮细胞相互作用的抗炎潜力，并阐明了这些影响的基本机制基础。HHT通过减少白细胞浸润和促炎细胞因子表达以及改善腹痛行为来影响小鼠腹膜炎模型中的体内炎症。体外，HT和HHT通过降低内皮细胞粘附分子胞内粘附分子-1（ICAM-1）和血管细胞粘附分子-1（VCAM-1）的表达来损害白细胞-内皮细胞的相互作用。这种作用是由两部分机制介导的。虽然HHT不影响显著的TNF诱导的促炎NF-B信号级联，该化合物以IRF-1依赖性方式下调了VCAM1mRNA的表达，并减少了活性的ICAM1mRNA翻译，如通过多聚体谱分析所确定的。这项研究强调了HHT作为一种抗炎化合物，通过靶向内皮激活过程有效地阻碍白细胞-内皮细胞相互作用。
