• Kenji Inoue, Mika Kobayashi, Kiichiro Yano, Mai Miura, Akashi Izumi, Chikage Mataki, Takeshi Doi, Takao Hamakubo, Patrick C Reid, David A Hume, Minoru Yoshida, William C Aird, Tatsuhiko Kodama, and Takashi Minami.
• 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 1;26(12):2652-9.

ObjectiveTumor 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.Methods And ResultsHuman 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.ConclusionsTNF-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.

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