title: High-mobility group box-1 and its receptors contribute to proinflammatory response in the acute phase of spinal cord injury in rats.
abstract: METHODS
  To examine the localization and expression of high-mobility group box-1 (HMGB-1) protein and its receptors after rat spinal cord injury.
  
  
  OBJECTIVE
  To elucidate the contribution of HMGB-1 and its receptors as potential candidates in a specific upstream pathway to the proinflammatory response leading to a cascade of secondary tissue damage after spinal cord injury.
  
  
  BACKGROUND
  HMGB-1 was recently characterized as a key cytokine with a potential role in nucleosome formation and regulation of gene transcription. No studies have investigated the role of HMGB-1 in spinal cord injury.
  
  
  METHODS
  Injured thoracic spinal cord from 62 rats aged 8 to 12 weeks and spinal cord from 20 control rats were examined. HMGB-1 was localized by immunofluorescence staining, costaining with cell markers, and by immunoelectron microscopy. The expression of HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)2, and TLR4 were also examined by immunohistochemistry.
  
  
  RESULTS
  HMGB-1 expression appeared earlier than that of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in the spinal cord injury rats, with the HMGB-1 produced by both macrophages and neurons. HMGB-1 translocated from nucleus to cytoplasm in some neurons at an early stage after neural injury. Increased expression of HMGB-1, RAGE, and TLRs was observed after injury, and interaction of HMGB-1 with RAGE or TLRs, particularly in macrophage, was confirmed at 3 days after injury.
  
  
  CONCLUSIONS
  Our results demonstrated an earlier onset in the expression of HMGB-1 than in tumor necrosis factor-α, IL-1β, and IL-6 after spinal cord injury. The release of HMGB-1 from neurons and macrophages is mediated through the HMGB-1/RAGE or TLR pathways. HMGB-1 seems to play at least some roles in the proinflammatory cascade originating the secondary damage after the initial spinal cord injury.
authors.affiliation: Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, The University of Fukui, Fukui, Japan.
authors.forename: Ke-Bing
authors.initials: KB
authors.lastname: Chen
authors.forename: Kenzo
authors.initials: K
authors.lastname: Uchida
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
authors.forename: Takafumi
authors.initials: T
authors.lastname: Yayama
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hirai
authors.forename: Alexander
authors.initials: A
authors.lastname: Rodriguez Guerrero
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Wei-Ying
authors.initials: WY
authors.lastname: Ma
authors.forename: Shao-Yu
authors.initials: SY
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Baba
mesh_terms: D000210:Acute-Phase Reaction / Q000209:etiology / Q000378:metabolism; D000818:Animals; D000870:Anterior Horn Cells / Q000378:metabolism / Q000648:ultrastructure; D016207:Cytokines / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D024243:HMGB1 Protein / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D016253:Microscopy, Immunoelectron; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000150:complications / Q000378:metabolism*; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha