title: Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice.
abstract: OBJECTIVE
  High mobility group box 1 (HMGB1) is an abundant protein that regulates chromosome architecture and also functions as a damage-associated molecular pattern molecule. Little is known about its intracellular roles in response to tissue injury or during subsequent local and systemic inflammatory responses. We investigated the function of Hmgb1 in mice after induction of acute pancreatitis.
  
  
  METHODS
  We utilized a Cre/LoxP system to create mice with pancreas-specific disruption in Hmbg1 (Pdx1-Cre; HMGB1(flox/flox) mice). Acute pancreatitis was induced in these mice (HMGB1(flox/flox) mice served as controls) after injection of l-arginine or cerulein. Pancreatic tissues and acinar cells were collected and analyzed by histologic, immunoblot, and immunohistochemical analyses.
  
  
  RESULTS
  After injection of l-arginine or cerulein, Pdx1-Cre; HMGB1(flox/flox) mice developed acute pancreatitis more rapidly than controls, with increased mortality. Pancreatic tissues of these mice also had higher levels of serum amylase, acinar cell death, leukocyte infiltration, and interstitial edema than controls. Pancreatic tissues and acinar cells collected from the Pdx1-Cre; HMGB1(flox/flox) mice after l-arginine or cerulein injection demonstrated nuclear catastrophe with greater nucleosome release when compared with controls, along with increased phosphorylation/activation of RELA nuclear factor κB, degradation of inhibitor of κB, and phosphorylation of mitogen-activated protein kinase. Inhibitors of reactive oxygen species (N-acetyl-l-cysteine) blocked l-arginine-induced DNA damage, necrosis, apoptosis, release of nucleosomes, and activation of nuclear factor κB in pancreatic tissues and acinar cells from Pdx1-Cre; HMGB1(flox/flox) and control mice. Exogenous genomic DNA and recombinant histone H3 proteins significantly induced release of HMGB1 from mouse macrophages; administration of antibodies against H3 to mice reduced serum levels of HMGB1 and increased survival after l-arginine injection.
  
  
  CONCLUSIONS
  In 2 mouse models of acute pancreatitis, intracellular HMGB1 appeared to prevent nuclear catastrophe and release of inflammatory nucleosomes to block inflammation. These findings indicate a role for the innate immune response in tissue damage.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: kangr@upmc.edu.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Wen
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Zhenwen
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Ruochan
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jillian
authors.initials: J
authors.lastname: Bonaroti
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Preeti
authors.initials: P
authors.lastname: Bansal
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Allan
authors.initials: A
authors.lastname: Tsung
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Qingde
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: David C
authors.initials: DC
authors.lastname: Whitcomb
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Eugene B
authors.initials: EB
authors.lastname: Chang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York.
authors.forename: Haichao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Ben
authors.initials: B
authors.lastname: Lu
authors.affiliation: Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Infectious Diseases, State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xue-Gong
authors.initials: XG
authors.lastname: Fan
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: lotzemt@upcm.edu.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: zehh@upmc.edu.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: tangd2@upmc.edu.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
mesh_terms: D000208:Acute Disease; D000818:Animals; D001120:Arginine; D016923:Cell Death; D002108:Ceruletide; D004249:DNA Damage; D004195:Disease Models, Animal; D006609:High Mobility Group Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009707:Nucleosomes / Q000378:metabolism*; D018384:Oxidative Stress; D010179:Pancreas / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: C486329:Hbp1 protein, mouse; D006609:High Mobility Group Proteins; D006657:Histones; D009707:Nucleosomes; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D002108:Ceruletide; D001120:Arginine
keywords: DNA Damage; Nuclear Factor κB; Oxidative Stress; Pancreatitis