title: Adeno-associated virus-mediated colonic secretory expression of HMGB1 A box attenuates experimental colitis in mice.
abstract: BACKGROUND
  Extracellular high mobility group box 1 (HMGB1) is crucially implicated in the pathogenesis of inflammatory bowel diseases (IBDs). A box domain of HMGB1 has been identified as a specific antagonist of HMGB1. In the present study, we tested the effects of adeno-associated virus (AAV)-mediated colonic secretory expression of HMGB1 A box on murine experimental colitis.
  
  
  METHODS
  Self-complementary AAV-2 carrying mouse immunoglobin Gκ leader-human HMGB1 A box (AAV-HMGB1 A box) was constructed. The effects of intracolonically administered AAV-HMGB1 A box on dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis were assessed by the disease activity index (DAI), colon length, macroscopic and histological scoring, myeloperoxidase (MPO) activity, and epithelial apoptosis and complementary proliferation. Colonic immune cell infiltrates, mucosal malondialdehyde content and superoxide dismutase activity, colonic tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-10 levels, serum HMGB1 concentration, and colonic HMGB1 release were determined to investigate the underlying mechanisms.
  
  
  RESULTS
  Intracolonically administered AAV-HMGB1 A box efficiently mediated secretory expression of HMGB1 A box and led to significant decreases in DAI, macroscopic and histological scores and colonic epithelial apoptosis in both DSS- and TNBS-treated mice. Modulating inflammation-associated cytokines, such as inhibiting colonic TNF-α and IL-1β expression, decreasing HMGB1 release, and restoring colonic IL-10 levels, and thereby inhibiting inflammatory cell infiltration and alleviating oxidant damage, might be the underlying mechanism.
  
  
  CONCLUSIONS
  Intracolonic application of AAV-HMGB1 A box is effective in alleviating murine colitis and has therapeutic potential in human IBDs.
authors: Department of Rheumatology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China.
authors: Xiaoyan
authors: X
authors: Zheng
authors: Department of Gastroenterology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi Province, People's Republic of China.
authors: Yifei
authors: Y
authors: Lv
authors: Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China.
authors: Shuang
authors: S
authors: Li
authors: Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China.
authors: Qiannan
authors: Q
authors: Zhang
authors: Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China.
authors: Xueting
authors: X
authors: Zhang
authors: Department of Rheumatology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China. haozhm66@126.com.|Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China. haozhm66@126.com.
authors: Zhiming
authors: Z
authors: Hao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D003106:Colon / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000378:metabolism; D024243:HMGB1 Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D009195:Peroxidase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D009195:Peroxidase; D013482:Superoxide Dismutase
keywords: 2,4,6-trinitrobenzene sulfonic acid; A box domain of high-mobility group box 1; colitis; dextran sulfate sodium; mice; self-complementary adeno-associated virus