Intracellular Hmgb1 Inhibits Inflammatory Nucleosome Release and Limits Acute Pancreatitis in Mice

被引：188

作者：

Kang, Rui ^{[1
]}

Zhang, Qiuhong ^{[1
]}

Hou, Wen ^{[1
]}

Yan, Zhenwen ^{[1
,2
]}

Chen, Ruochan ^{[1
]}

Bonaroti, Jillian ^{[1
]}

Bansal, Preeti ^{[1
]}

Billiar, Timothy R. ^{[1
]}

Tsung, Allan ^{[1
]}

Wang, Qingde ^{[1
]}

Bartlett, David L. ^{[1
]}

Whitcomb, David C. ^{[3
]}

Chang, Eugene B. ^{[4
]}

Zhu, Xiaorong ^{[4
]}

Wang, Haichao ^{[5
]}

Lu, Ben ^{[6
]}

Tracey, Kevin J. ^{[6
]}

Cao, Lizhi ^{[7
]}

Fan, Xue-Gong ^{[8
]}

Lotze, Michael T. ^{[1
]}

Zeh, Herbert J., III ^{[1
]}

Tang, Daolin ^{[1
]}

机构：

[1] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15213 USA

[2] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Neurol, Guangzhou 510275, Guangdong, Peoples R China

[3] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA

[4] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[5] N Shore Univ Hosp, Dept Emergency Med, Manhasset, NY USA

[6] Feinstein Inst Med Res, Lab Biomed Sci, Manhasset, NY USA

[7] Cent S Univ, Dept Pediat, Xiangya Hosp, Changsha, Hunan, Peoples R China

[8] Cent S Univ, Dept Infect Dis, State Key Lab Viral Hepatitis, Xiangya Hosp, Changsha, Hunan, Peoples R China

来源：

GASTROENTEROLOGY | 2014年 / 146卷 / 04期

基金：

美国国家卫生研究院;

关键词：

DNA Damage; Pancreatitis; Oxidative Stress; Nuclear Factor kappa B; NF-KAPPA-B; GROUP BOX CHROMOSOMAL-PROTEIN-1; LIVER ISCHEMIA; ORGAN INJURY; RECEPTOR; ACTIVATION; CELLS; DNA; PATHOGENESIS; APOPTOSIS;

D O I：

10.1053/j.gastro.2013.12.015

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 kB, degradation of inhibitor of kB, 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 kB 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.

引用

页码：1097 / U338

页数：19

共 57 条

[1] Histones from Dying Renal Cells Aggravate Kidney Injury via TLR2 and TLR4 [J].