Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice.
Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice.
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DOI：
10.1053/j.gastro.2013.12.015
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发表时间：
2014-04
期刊：
影响因子：
29.4
通讯作者：
Tang D
中科院分区：
文献类型：
--
作者：
Kang R;Zhang Q;Hou W;Yan Z;Chen R;Bonaroti J;Bansal P;Billiar TR;Tsung A;Wang Q;Bartlett DL;Whitcomb DC;Chang EB;Zhu X;Wang H;Lu B;Tracey KJ;Cao L;Fan XG;Lotze MT;Zeh HJ 3rd;Tang D
高迁移率组框1 （HMGB1）是一种丰富的调节染色体结构的蛋白质，也是一种与损伤相关的分子模式分子。对于其在组织损伤反应或随后的局部和全身炎症反应中的细胞内作用知之甚少。我们研究了Hmgb1在小鼠急性胰腺炎诱导后的功能。我们利用Cre/LoxP系统创建了Hmbg1 （Pdx1-Cre； HMGB1flox/flox小鼠）中胰腺特异性破坏的小鼠。这些小鼠（HMGB1flox/flox小鼠作为对照）在注射l -精氨酸或蓝蛋白后诱导急性胰腺炎。收集胰腺组织和腺泡细胞并进行组织学、免疫印迹和免疫组织化学分析。注射l -精氨酸或丙氨酸后，Pdx1-Cre；HMGB1flox/flox小鼠比对照组更快地发生急性胰腺炎，死亡率增加。与对照组相比，这些小鼠胰腺组织的血清淀粉酶、腺泡细胞死亡、白细胞浸润和间质水肿水平也较高。Pdx1-Cre胰腺组织和腺泡细胞；与对照组相比，注射l -精氨酸或蓝蛋白后的HMGB1flox/flox小鼠表现出核突变，核小体释放增加，RELA Nfκb磷酸化/活化增加，Iκb降解增加，Mapk磷酸化增加。活性氧（n -乙酰- l-半胱氨酸）抑制剂阻断l-精氨酸诱导的Pdx1-Cre胰腺组织和腺泡细胞DNA损伤、坏死、凋亡、核小体释放和Nfκb活化；HMGB1flox/flox和对照小鼠。外源性基因组DNA和重组组蛋白H3显著诱导小鼠巨噬细胞释放HMGB1；给小鼠注射抗H3抗体可降低血清HMGB1水平，提高l -精氨酸注射后的存活率。在2种急性胰腺炎小鼠模型中，细胞内HMGB1似乎可以阻止核突变，并释放炎症核小体来阻断炎症。这些发现表明先天免疫反应在组织损伤中的作用。
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 following induction of acute pancreatitis. We utilized a Cre/LoxP system to create mice with pancreas-specific disruption in Hmbg1 (Pdx1-Cre; HMGB1flox/flox mice). Acute pancreatitis was induced in these mice (HMGB1flox/flox mice served as controls) following injection of L-arginine or cerulein. Pancreatic tissues and acinar cells were collected and analyzed by histologic, immunoblot, and immunohistochemical analyses. Following injection of L-arginine or cerulein, Pdx1-Cre; HMGB1flox/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; HMGB1flox/flox mice following L-arginine- or cerulein injection demonstrated nuclear catastrophe with greater nucleosome release when compared with controls, along with increased phosphorylation/activation of RELA Nfκb, degradation of Iκb, and phosphorylation of Mapk. Inhibitors of reactive oxygen species (N-acetyl-L-cysteine) blocked L-arginine–induced DNA damage, necrosis, apoptosis, release of nucleosomes, and activation of Nfκb in pancreatic tissues and acinar cells from Pdx1-Cre; HMGB1flox/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 following L-arginine injection. 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.
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影响因子：
30.8
作者：
Calogero, S;Grassi, F;Bianchi, ME
通讯作者：
Bianchi, ME
影响因子：
8
作者：
Kang, R.;Tang, D.;Zeh, H. J.
通讯作者：
Zeh, H. J.
DOI：
10.1152/ajpgi.00167.2006
发表时间：
2007-04-01
影响因子：
4.5
作者：
Dawra, Rajinder;Sharif, Rifat;Saluja, Ashok K.
通讯作者：
Saluja, Ashok K.
影响因子：
3.6
作者：
Kocsis, A. K.;Szabolcs, A.;Mandi, Y.
通讯作者：
Mandi, Y.
影响因子：
2.2
作者：
Li, JH;Wang, HC;Yang, H
通讯作者：
Yang, H