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Gastroenterology. 2014 Apr;146(4):1097-107. doi: 10.1053/j.gastro.2013.12.015. Epub 2013 Dec 17.

Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice.

Author information

1
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: kangr@upmc.edu.
2
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
3
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
4
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
5
Department of Medicine, University of Chicago, Chicago, Illinois.
6
Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York.
7
Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York.
8
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
9
Department of Infectious Diseases, State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
10
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: lotzemt@upcm.edu.
11
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: zehh@upmc.edu.
12
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: tangd2@upmc.edu.

Abstract

BACKGROUND & AIMS:

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.

KEYWORDS:

DNA Damage; Nuclear Factor κB; Oxidative Stress; Pancreatitis

PMID:
24361123
PMCID:
PMC3965592
DOI:
10.1053/j.gastro.2013.12.015
[Indexed for MEDLINE]
Free PMC Article

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