Inoue Kenji, Kobayashi Mika, Yano Kiichiro, Miura Mai, Izumi Akashi, Mataki Chikage, Doi Takeshi, Hamakubo Takao, Reid Patrick C, Hume David A, Yoshida Minoru, Aird William C, Kodama Tatsuhiko, Minami Takashi
Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguro, Tokyo, 153-8904, Japan.
Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2652-9. doi: 10.1161/01.ATV.0000247247.89787.e7. Epub 2006 Sep 28.
Tumor necrosis factor (TNF)-alpha initiates numerous changes in endothelial cell (EC) gene expression that contributes to the pathology of various diseases including inflammation. We hypothesized that TNF-alpha-mediated gene induction involves multiple signaling pathways, and that inhibition of one or more of these pathways may selectively target subsets of TNF-alpha-responsive genes and functions.
Human umbilical vein endothelial cells (ECs) were preincubated with inhibitors of PI3 kinase (LY294002), histone deacetylases (HDAC) (trichostatin A [TSA]), de novo protein synthesis (CHX), proteasome (MG-132), and GATA factors (K-11430) before exposure to TNF-alpha at 4 hours and analyzed by microarray. TNF-alpha-mediated induction of vascular cell adhesion molecule-1 (VCAM-1) was attenuated by all of these inhibitors, whereas in contrast, stimulation of intercellular adhesion molecule-1 (ICAM-1) was blocked by MG-132 alone. Moreover TSA blocked TNF-alpha-mediated induction of monocyte adhesion both in vitro and in vivo through the suppression of VCAM-1. Further analysis demonstrated that HDAC3 plays a significant role in the regulation of TNF-alpha-mediated VCAM-1 expression.
TNF-alpha activates ECs via multiple signaling pathways, and these pathways may be selectively targeted to modulate EC function. Moreover, TSA treatment reduced monocyte adhesion via VCAM-1 suppression in vitro and in vivo, suggesting that TSA might be useful for the attenuation of the inflammatory response in EC.
肿瘤坏死因子（TNF）-α可引发内皮细胞（EC）基因表达的众多变化，这些变化与包括炎症在内的多种疾病的病理过程相关。我们推测TNF-α介导的基因诱导涉及多种信号通路，抑制其中一条或多条通路可能会选择性地靶向TNF-α反应性基因和功能的亚群。
人脐静脉内皮细胞（ECs）在暴露于TNF-α 4小时前，先用磷脂酰肌醇-3激酶（PI3激酶）抑制剂（LY294002）、组蛋白去乙酰化酶（HDAC）抑制剂（曲古抑菌素A [TSA]）、蛋白质从头合成抑制剂（放线菌酮 [CHX]）、蛋白酶体抑制剂（MG-132）和GATA因子抑制剂（K-11430）进行预孵育，然后通过微阵列分析。所有这些抑制剂均减弱了TNF-α介导的血管细胞黏附分子-1（VCAM-1）的诱导，而相反，细胞间黏附分子-1（ICAM-1）的刺激仅被MG-132阻断。此外，TSA通过抑制VCAM-1在体外和体内均阻断了TNF-α介导的单核细胞黏附。进一步分析表明，HDAC3在TNF-α介导的VCAM-1表达调控中起重要作用。
TNF-α通过多种信号通路激活内皮细胞，这些通路可能被选择性靶向以调节内皮细胞功能。此外，TSA处理通过在体外和体内抑制VCAM-1减少了单核细胞黏附，表明TSA可能有助于减轻内皮细胞中的炎症反应。
