title: Histone deacetylase inhibitor reduces monocyte adhesion to endothelium through the suppression of vascular cell adhesion molecule-1 expression.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Kenji
authors.initials: K
authors.lastname: Inoue
authors.forename: Mika
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Yano
authors.forename: Mai
authors.initials: M
authors.lastname: Miura
authors.forename: Akashi
authors.initials: A
authors.lastname: Izumi
authors.forename: Chikage
authors.initials: C
authors.lastname: Mataki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Doi
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Reid
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: William C
authors.initials: WC
authors.lastname: Aird
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Takashi
authors.initials: T
authors.lastname: Minami
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D000099186:Histone Deacetylase 3
chemical_list: D001381:Azepines; D002867:Chromones; D019040:E-Selectin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D018799:Intercellular Adhesion Molecule-1; D007976:Leupeptins; D009025:Morpholines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000099186:Histone Deacetylase 3; C515615:K 11430; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C012589:trichostatin A; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde