title: Inflammatory cytokines induce MAdCAM-1 in murine hepatic endothelial cells and mediate alpha-4 beta-7 integrin dependent lymphocyte endothelial adhesion in vitro.
abstract: BACKGROUND
  MAdCAM-1 plays a central role in T-lymphocyte homing to the gut, but its role in chronic liver inflammation remains unknown. Therefore, this study measured MAdCAM-1 expression, regulation, and function in cultured murine hepatic endothelial cells.
  
  
  METHODS
  Cultures of hepatic endothelial cells (HEC) were prepared from mice expressing a temperature-sensitive SV40 large T antigen (H-2Kb-tsA58) under the control of an IFN-gamma promoter. Time and dose dependent expression of MAdCAM-1 in response to TNF-alpha, IL-1 beta and IFN-gamma was studied by immunoblotting. Lymphocyte adhesion was studied using alpha 4 beta 7 integrin expressing lymphocytes (TK-1) +/- anti-MAdCAM-1 mAb.
  
  
  RESULTS
  TNF-alpha induced MAdCAM-1 dose-and time-dependently with maximum expression at 20 ng/ml and at 48 hours. IL-1 beta also induced MAdCAM-1 to a lesser extent compared to TNF-alpha; IFN-gamma did not induce MAdCAM-1. TNF-alpha significantly increased lymphocyte-endothelial adhesion (P < 0.01), which was reversed by anti-MAdCAM-1 antibody. MAdCAM-1 expression was also reduced by N-acetylcysteine and by two NO donors (SperNO, DETANO) suggesting that hepatic endothelial MAdCAM-1 is oxidant and NO regulated.
  
  
  CONCLUSIONS
  MAdCAM-1 is a major determinant of leukocyte recruitment in chronic inflammation and is expressed by HEC in response to IL-1 beta and TNF-alpha. This system may provide a useful model for studying inflammatory mechanisms in liver disease and help determine if controlled MAdCAM-1 expression might influence inflammation in liver disease.
authors.affiliation: Nagoya City Medical University, 1-Kawasumi-Mizuho, Nagoya, 467-8601, Japan. andytomo@hotmail.com
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ando
authors.forename: Robert R
authors.initials: RR
authors.lastname: Langley
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wang
authors.forename: Paul A
authors.initials: PA
authors.lastname: Jordan
authors.forename: Alireza
authors.initials: A
authors.lastname: Minagar
authors.forename: J Steven
authors.initials: JS
authors.lastname: Alexander
authors.forename: Merilyn H
authors.initials: MH
authors.lastname: Jennings
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D004729:Endothelium, Lymphatic / Q000166:cytology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000502:physiology*; D016023:Integrins / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009088:Mucoproteins
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D018836:Inflammation Mediators; D016023:Integrins; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; C071777:integrin alpha4beta7