Targeting Endothelial Adhesion Molecule Transcription for Treatment of Inflammatory Disease: A Proof-of-Concept Study.
Targeting Endothelial Adhesion Molecule Transcription for Treatment of Inflammatory Disease: A Proof-of-Concept Study.
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DOI：
10.1155/2016/7945848
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发表时间：
2016
影响因子：
4.6
通讯作者：
Smith JR
中科院分区：
文献类型：
--
作者：
Ashander LM;Appukuttan B;Ma Y;Gardner-Stephen D;Smith JR
靶向控制白细胞运输到组织中的内皮粘附分子已被探索作为炎性疾病的生物疗法。然而，这些分子也参与白细胞迁移的免疫监视，抑制粘附分子的生理水平可能会促进感染或恶性肿瘤。我们探讨了在人类系统炎症过程中靶向内皮粘附分子转录的概念。非感染性后葡萄膜炎中细胞间粘附分子1（ICAM-1）介导白细胞迁移通过视网膜内皮。我们观察到，在用肿瘤坏死因子-α（TNF-α）处理的人视网膜内皮细胞中，B细胞核因子κ轻链多肽基因增强子1（NF-κB1）与ICAM-1平行增加，并确定了ICAM-1调节区内NF-κB1的假定结合位点。我们用小干扰RNA（siRNA）靶向诱导内皮细胞NF-κB1的表达。NF-κB1的敲除可显著降低TNF-α诱导的细胞表面ICAM-1蛋白表达，但不降低ICAM-1的组成性表达。同样，NF-κB1敲低显著降低了TNF-α存在下白细胞与细胞单层的结合，但不影响基线结合。这项概念验证研究的结果表明，内皮粘附分子的诱导转录可能是人类炎症性疾病的治疗靶点。
Targeting the endothelial adhesion molecules that control leukocyte trafficking into a tissue has been explored as a biological therapy for inflammatory diseases. However, these molecules also participate in leukocyte migration for immune surveillance, and inhibiting the physiological level of an adhesion molecule might promote infection or malignancy. We explored the concept of targeting endothelial adhesion molecule transcription during inflammation in a human system. Intercellular adhesion molecule 1 (ICAM-1) mediates leukocyte migration across the retinal endothelium in noninfectious posterior uveitis. We observed an increase in the transcription factor, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1), in parallel with ICAM-1, in human retinal endothelial cells treated with tumor necrosis factor-alpha (TNF-α), and identified putative binding sites for NF-κB1 within the ICAM-1 regulatory region. We targeted induced NF-κB1 expression in endothelial cells with small interfering (si)RNA. Knockdown of NF-κB1 significantly decreased cell surface expression of ICAM-1 protein induced by TNF-α but did not reduce constitutive ICAM-1 expression. Consistently, NF-κB1 knockdown significantly reduced leukocyte binding to cell monolayers in the presence of TNF-α but did not impact baseline binding. Findings of this proof-of-concept study indicate that induced transcription of endothelial adhesion molecules might be targeted therapeutically for inflammatory disease in humans.