title: Recombinant Thrombomodulin Modulates Murine Colitis Possibly via High-Mobility Group Box 1 Protein Inhibition.
abstract: OBJECTIVE
  Thrombomodulin (TM) is an anticoagulant cofactor protein. We hypothesized that its recombinant soluble TM (rhTM) form, widely used to treat disseminated intravascular coagulation, might have anti-inflammatory action in inflammatory bowel disease (IBD), possibly through its inhibition of high-mobility group box 1 protein (HMGB1).
  
  
  METHODS
  We investigated inflammatory effects of HMGB1 and anti-inflammatory effect of rhTM in dextran sulfate sodium (DSS)-treated mice, some cell lines and ulcerative colitis (UC) patients, particularly focusing on changes of vascular endothelial adhesion molecules.
  
  
  RESULTS
  Treatments with rhTM significantly attenuated DSS-treated mice clinically and histologically. The mRNA levels of proinflammatory cytokines and adhesion molecules were decreased by rhTM. Increased inflammatory cells in the colonic mucosa strongly expressed HMGB1 in the cytoplasm in the DSS-treated mice and UC patients' colonic mucosa, which were significantly decreased by rhTM in mice. In in vitro experiments, rhTM significantly decreased the mRNA levels of tumor necrosis factor-alpha (TNF-α) and adhesion molecules increased by endotoxin exposures in RAW 264.7 (macrophage cell line) and bEND.3 cells (endothelial cell line), suggesting the proinflammatory role of HMGB1 in TNF-α production from macrophages.
  
  
  CONCLUSIONS
  These findings suggest that rhTM may be useful for the treatment of IBD by attenuating inflammatory cytokine production and adhesion molecule expression, partly because of its inhibition of HMGB1.
authors: Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
authors: Toshihide
authors: T
authors: Ueda
authors: Masaaki
authors: M
authors: Higashiyama
authors: Kazuyuki
authors: K
authors: Narimatsu
authors: Yuichi
authors: Y
authors: Yasutake
authors: Chie
authors: C
authors: Kurihara
authors: Yoshikiyo
authors: Y
authors: Okada
authors: Chikako
authors: C
authors: Watanabe
authors: Kenichi
authors: K
authors: Yoshikawa
authors: Koji
authors: K
authors: Maruta
authors: Shunsuke
authors: S
authors: Komoto
authors: Kengo
authors: K
authors: Tomita
authors: Shigeaki
authors: S
authors: Nagao
authors: Ryota
authors: R
authors: Hokari
authors: Soichiro
authors: S
authors: Miura
mesh_terms: D000328:Adult; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D002460:Cell Line; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D018180:Thrombomodulin / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D016207:Cytokines; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; D012333:RNA, Messenger; D011994:Recombinant Proteins; C546931:THBD protein, human; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D016264:Dextran Sulfate