title: Thrombomodulin modulates dendritic cells via both antagonism of high mobility group protein B1 and an independent mechanism.
abstract: BACKGROUND
  Thrombomodulin treatment modulates the properties of dendritic cells (DCs) converting them from immunogenic to tolerogenic and inducing its own expression on DCs. Thrombomodulin binds to the inflammatory mediator, high mobility group protein B1 (HMGB1), antagonizing signalling through its receptor, receptor for advanced glycation end products (RAGE).
  
  
  METHODS
  To test if soluble thrombomodulin could antagonize HMGB1 signaling via RAGE on DCs. DCs were prepared from mouse bone marrow cells or human monocytes. In some experiments dendritic cells were sorted into thrombomodulin+ and thrombomodulin- populations. Expression of surface maturation markers was determined by flow cytometry following treatment with thrombomodulin in the presence or absence of HMGB1.
  
  
  RESULTS
  Thrombomodulin+ dendritic cells secrete less HMGB1 into the medium. HMGB1 reduces the effects of thrombomodulin on expression of DC maturation markers. Treatment with thrombomodulin reduces the expression of maturation markers such as CD80 and CD86 and increases the expression of thrombomodulin on the DC surface. Treatment of DCs with neutralizing anti-HMGB1 antibody acted synergistically with thrombomodulin in increasing thrombomodulin expression on DCs. Treatment with thrombomodulin can still reduce the expression of surface markers on DCs derived from mice that are deficient in RAGE showing that thrombomodulin can affect DCs by an alternative mechanism.
  
  
  CONCLUSIONS
  The results of this study show that thrombomodulin modulates DCs both by antagonizing the interaction of HMGB1 with RAGE and by an independent mechanism.
authors.affiliation: Department of Immunology, Mie University School of Medicine, Mie, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
authors.affiliation: Department of Immunology, Mie University School of Medicine, Mie, Japan; Department of Pulmonary and Critical Care Medicine, Mie University School of Medicine, Mie, Japan.
authors.forename: Corina N
authors.initials: CN
authors.lastname: D'Alessandro-Gabazza
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Mie University School of Medicine, Mie, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Takagi
authors.affiliation: Department of Immunology, Mie University School of Medicine, Mie, Japan.
authors.forename: Ayshwarya-Lakshmi
authors.initials: AL
authors.lastname: Chelakkot-Govindalayathila
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Mie University School of Medicine, Mie, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Taguchi
authors.affiliation: Department of Immunology, Mie University School of Medicine, Mie, Japan.
authors.forename: Ziaurahman
authors.initials: Z
authors.lastname: Roeen
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Munesue
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Immunology, Mie University School of Medicine, Mie, Japan.
authors.forename: Esteban C
authors.initials: EC
authors.lastname: Gabazza
authors.affiliation: Department of Immunology, Mie University School of Medicine, Mie, Japan; Division of Hematology, Stanford University School of Medicine, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Morser
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D018180:Thrombomodulin / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D024243:HMGB1 Protein; D011994:Recombinant Proteins; D018180:Thrombomodulin