Activation of gene expression in human neutrophils by high mobility group box 1 protein

2003 ◽  
Vol 284 (4) ◽  
pp. C870-C879 ◽  
Author(s):  
Jong Sung Park ◽  
John Arcaroli ◽  
Ho-Kee Yum ◽  
Huan Yang ◽  
Haichao Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Injury ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Gene Expression Pattern ◽  
High Mobility ◽  
Neutrophil Activation ◽  
High Mobility Group ◽  
Human Neutrophils ◽  
Hmgb1 Protein

High mobility group box 1 (HMGB1) protein, a DNA binding protein that stabilizes nucleosomes and facilitates transcription, was recently identified as a late mediator of endotoxin lethality. High serum HMGB1 levels in patients with sepsis are associated with increased mortality, and administration of HMGB1 produces acute inflammation in animal models of lung injury and endotoxemia. Neutrophils occupy a critical role in mediating the development of endotoxemia-associated acute lung injury, but previously it was not known whether HMGB1 could influence neutrophil activation. In the present experiments, we demonstrate that HMGB1 increases the nuclear translocation of NF-κB and enhances the expression of proinflammatory cytokines in human neutrophils. These proinflammatory effects of HMGB1 in neutrophils appear to involve the p38 MAPK, phosphatidylinositol 3-kinase/Akt, and ERK1/2 pathways. The mechanisms of HMGB1-induced neutrophil activation are distinct from endotoxin-induced signals, because HMGB1 leads to a different profile of gene expression, pattern of cytokine expression, and kinetics of p38 activation compared with LPS. These findings indicate that HMGB1 is an effective stimulus of neutrophil activation that can contribute to development of a proinflammatory phenotype in diseases characterized by excessively high levels of HMGB1.

α-Chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis

2005 ◽  
Vol 289 (4) ◽  
pp. L583-L590 ◽  
Author(s):  
Xinchun Lin ◽  
Huan Yang ◽  
Tohru Sakuragi ◽  
Maowen Hu ◽  
Lin L. Mantell ◽  
...  
Keyword(s):  
Lung Injury ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Critical Role ◽  
High Mobility ◽  
High Mobility Group ◽  
Receptor Blockade ◽  
Inflammatory Injury ◽  
Receptor Inhibition

High mobility group box 1 (HMGB1) protein, a late mediator of lethality in sepsis, can induce acute inflammatory lung injury. Here, we identify the critical role of α-chemokine receptors in the HMGB1-induced inflammatory injury and show that α-chemokine receptor inhibition increases survival in sepsis, in a clinically relevant time frame. Intratracheal instillation of recombinant HMGB1 induces a neutrophilic leukocytosis, preceded by alveolar accumulation of the α-chemokine macrophage inflammatory protein-2 and accompanied by injury and increased inflammatory potential within the air spaces. To investigate the role of α-chemokine receptors in the injury, we instilled recombinant HMGB1 (0.5 μg) directly into the lungs and administered a subcutaneous α-chemokine receptor inhibitor, Antileukinate (200 μg). α-Chemokine receptor blockade reduced HMGB1-induced inflammatory injury (neutrophils: 2.9 ± 3.2 vs. 8.1 ± 2.4 × 104cells; total protein: 120 ± 48 vs. 311 ± 129 μg/ml; reactive nitrogen species: 2.3 ± 0.3 vs. 3.5 ± 1.3 μM; and macrophage migration inhibitory factor: 6.4 ± 4.2 vs. 37.4 ± 15.9 ng/ml) within the bronchoalveolar lavage fluid, indicating that HMGB1-induced inflammation and injury are α-chemokine mediated. Because HMGB1 can mediate late septic lethality, we administered Antileukinate to septic mice and observed increased survival (from 58% in controls to 89%) even when the inhibitor treatment was initiated 24 h after the induction of sepsis. These data demonstrate that α-chemokine receptor inhibition can reduce HMGB1-induced lung injury and lethality in established sepsis and may provide a novel treatment in this devastating disease.

PECAM-1-dependent heme oxygenase-1 regulation via an Nrf2-mediated pathway in endothelial cells

2014 ◽  
Vol 111 (06) ◽  
pp. 1077-1088 ◽  
Author(s):  
Yarúa Jaimes ◽  
Ananta Paine ◽  
Constanca Figueiredo ◽  
Britta Eiz-Vesper ◽  
Rainer Blasczyk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Heme Oxygenase ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Chinese Hamster ◽  
Human Neutrophils ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Functional Link

SummaryThe antioxidant enzyme heme oxygenase (HO)-1, which catalyses the first and rate-limiting step of heme degradation, has major anti-inflammatory and immunomodulatory effects via its cell-type-specific functions in the endothelium. In the current study, we investigated whether the key endothelial adhesion and signalling receptor PECAM-1 (CD31) might be involved in the regulation of HO-1 gene expression in human endothelial cells (ECs). To this end PECAM-1 expression was down-regulated in human umbilical vein ECs (HUVECs) by an adenoviral vector-based knockdown approach. PECAM-1 knockdown markedly induced HO-1, but not the constitutive HO isoform HO-2. Nuclear translocation of the transcription factor NF-E2-related factor-2 (Nrf2), which is a master regulator of the inducible antioxidant cell response, and intracellular levels of reactive oxygen species (ROS) were increased in PECAM-1-deficient HUVECs, respectively. PECAM-1-dependent HO-1 regulation was also examined in PECAM-1 over-expressing Chinese hamster ovary and murine L-cells. Endogenous HO-1 gene expression and reporter gene activity of transiently transfected luciferase HO-1 promoter constructs with Nrf2 target sequences were decreased in PECAM-1 over-expressing cells. Moreover, a regulatory role of ROS for HO-1 regulation in these cells is demonstrated by studies with the antioxidant N-acetylcysteine and exogenous hydrogenperoxide. Finally, direct interaction of PECAM-1 with a native complex of its binding partner NB1 (CD177) and serine proteinase 3 (PR3) from human neutrophils, markedly induced HO-1 expression in HUVECs. Taken together, we demonstrate a functional link between HO-1 gene expression and PECAM-1 in human ECs, which might play a critical role in the regulation of inflammation.

scholarly journals Characterization of an Entamoeba histolytica High-Mobility-Group Box Protein Induced during Intestinal Infection

2008 ◽  
Vol 7 (9) ◽  
pp. 1565-1572 ◽  
Author(s):  
Mayuresh M. Abhyankar ◽  
Amelia E. Hochreiter ◽  
Jessica Hershey ◽  
Clive Evans ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Entamoeba Histolytica ◽  
Mutational Analysis ◽  
High Mobility ◽  
High Mobility Group ◽  
Unicellular Eukaryote ◽  
Hmgb1 Protein ◽  
A Genome ◽  
Hmgb Proteins

ABSTRACT The unicellular eukaryote Entamoeba histolytica is a human parasite that causes amebic dysentery and liver abscess. A genome-wide analysis of gene expression modulated by intestinal colonization and invasion identified an upregulated transcript that encoded a putative high-mobility-group box (HMGB) protein, EhHMGB1. We tested if EhHMGB1 encoded a functional HMGB protein and determined its role in control of parasite gene expression. Recombinant EhHMGB1 was able to bend DNA in vitro, a characteristic of HMGB proteins. Core conserved residues required for DNA bending activity in other HMGB proteins were demonstrated by mutational analysis to be essential for EhHMGB1 activity. EhHMGB1 was also able to enhance the binding of human p53 to its cognate DNA sequence in vitro, which is expected for an HMGB1 protein. Confocal microscopy, using antibodies against the recombinant protein, confirmed its nuclear localization. Overexpression of EhHMGB1 in HM1:IMSS trophozoites led to modulation of 33 transcripts involved in a variety of cellular functions. Of these, 20 were also modulated at either day 1 or day 29 in the mouse model of intestinal amebiasis. Notably, four transcripts with known roles in virulence, including two encoding Gal/GalNAc lectin light chains, were modulated in response to EhHMGB1 overexpression. We concluded that EhHMGB1 was a bona fide HMGB protein with the capacity to recapitulate part of the modulation of parasite gene expression seen during adaptation to the host intestine.

scholarly journals Deficiency of the novel high mobility group protein HMGXB4 protects against systemic inflammation-induced endotoxemia in mice

2021 ◽  
Vol 118 (7) ◽  
pp. e2021862118
Author(s):  
Xiangqin He ◽  
Kunzhe Dong ◽  
Jian Shen ◽  
Guoqing Hu ◽  
Jinhua Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Critical Role ◽  
Cecal Ligation ◽  
High Mobility ◽  
High Mobility Group ◽  
No Production ◽  
High Mobility Group Protein ◽  
Pulmonary Vascular Permeability ◽  
Proinflammatory Gene

Sepsis is a major cause of mortality in intensive care units, which results from a severely dysregulated inflammatory response that ultimately leads to organ failure. While antibiotics can help in the early stages, effective strategies to curtail inflammation remain limited. The high mobility group (HMG) proteins are chromosomal proteins with important roles in regulating gene transcription. While HMGB1 has been shown to play a role in sepsis, the role of other family members including HMGXB4 remains unknown. We found that expression of HMGXB4 is strongly induced in response to lipopolysaccharide (LPS)-elicited inflammation in murine peritoneal macrophages. Genetic deletion of Hmgxb4 protected against LPS-induced lung injury and lethality and cecal ligation and puncture (CLP)-induced lethality in mice, and attenuated LPS-induced proinflammatory gene expression in cultured macrophages. By integrating genome-wide transcriptome profiling and a publicly available ChIP-seq dataset, we identified HMGXB4 as a transcriptional activator that regulates the expression of the proinflammatory gene, Nos2 (inducible nitric oxide synthase 2) by binding to its promoter region, leading to NOS2 induction and excessive NO production and tissue damage. Similar to Hmgxb4 ablation in mice, administration of a pharmacological inhibitor of NOS2 robustly decreased LPS-induced pulmonary vascular permeability and lethality in mice. Additionally, we identified the cell adhesion molecule, ICAM1, as a target of HMGXB4 in endothelial cells that facilitates inflammation by promoting monocyte attachment. In summary, our study reveals a critical role of HMGXB4 in exacerbating endotoxemia via transcriptional induction of Nos2 and Icam1 gene expression and thus targeting HMGXB4 may be an effective therapeutic strategy for the treatment of sepsis.

High Mobility Group Box-1 (HMGB1): A Potential Target in Therapeutics

2019 ◽  
Vol 20 (14) ◽  
pp. 1474-1485 ◽  
Author(s):  
Eyaldeva C. Vijayakumar ◽  
Lokesh Kumar Bhatt ◽  
Kedar S. Prabhavalkar
Keyword(s):  
Myocardial Infarction ◽  
Vagus Nerve Stimulation ◽  
Nuclear Protein ◽  
Therapeutic Potential ◽  
High Mobility ◽  
Dna Binding Protein ◽  
High Mobility Group ◽  
Eukaryotic Cells ◽  
Hmgb1 Protein

High mobility group box-1 (HMGB1) mainly belongs to the non-histone DNA-binding protein. It has been studied as a nuclear protein that is present in eukaryotic cells. From the HMG family, HMGB1 protein has been focused particularly for its pivotal role in several pathologies. HMGB-1 is considered as an essential facilitator in diseases such as sepsis, collagen disease, atherosclerosis, cancers, arthritis, acute lung injury, epilepsy, myocardial infarction, and local and systemic inflammation. Modulation of HMGB1 levels in the human body provides a way in the management of these diseases. Various strategies, such as HMGB1-receptor antagonists, inhibitors of its signalling pathway, antibodies, RNA inhibitors, vagus nerve stimulation etc. have been used to inhibit expression, release or activity of HMGB1. This review encompasses the role of HMGB1 in various pathologies and discusses its therapeutic potential in these pathologies.

scholarly journals High-Mobility Group Box 1 (HMGB1) and Autophagy in Acute Lung Injury (ALI): A Review

2019 ◽  
Vol 25 ◽  
pp. 1828-1837 ◽  
Author(s):  
Lihua Qu ◽  
Chao Chen ◽  
YangYe Chen ◽  
Yi Li ◽  
Fang Tang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
High Mobility ◽  
High Mobility Group

scholarly journals In vitro and in vivo assessment of the protective effect of sufentanil in acute lung injury

2021 ◽  
Vol 49 (2) ◽  
pp. 030006052098635
Author(s):  
Qi Gao ◽  
Ningqing Chang ◽  
Donglian Liu
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protective Effect ◽  
High Mobility ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Hmgb1 Protein

Objectives To investigate the mechanisms underlying the protective effect of sufentanil against acute lung injury (ALI). Material and Methods Rats were administered lipopolysaccharide (LPS) by endotracheal instillation to establish a model of ALI. LPS was used to stimulate BEAS-2B cells. The targets and promoter activities of IκB were assessed using a luciferase reporter assay. Apoptosis of BEAS-2B cells was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Results Sufentanil treatment markedly reduced pathological changes in lung tissue, pulmonary edema and secretion of inflammatory factors associated with ALI in vivo and in vitro. In addition, sufentanil suppressed apoptosis induced by LPS and activated NF-κB both in vivo and in vitro. Furthermore, upregulation of high mobility group box protein 1 (HMGB1) protein levels and downregulation of miR-129-5p levels were observed in vivo and in vitro following sufentanil treatment. miR-129-5p targeted the 3ʹ untranslated region and its inhibition decreased promoter activities of IκB-α. miR-129-5p inhibition significantly weakened the protective effect of sufentanil on LPS-treated BEAS-2B cells. Conclusion Sufentanil regulated the miR-129-5p/HMGB1 axis to enhance IκB-α expression, suggesting that sufentanil represents a candidate drug for ALI protection and providing avenues for clinical treatment.

Therapeutic potential of recombinant thrombomodulin for lung injury after pneumonectomy via inhibition of high-mobility group box 1 in mice

2016 ◽  
Vol 81 (5) ◽  
pp. 868-875 ◽  
Author(s):  
Yusuke Takahashi ◽  
Noriyuki Matsutani ◽  
Hitoshi Dejima ◽  
Takashi Nakayama ◽  
Ryo Okamura ◽  
...  
Keyword(s):  
Lung Injury ◽  
Therapeutic Potential ◽  
High Mobility ◽  
High Mobility Group ◽  
Recombinant Thrombomodulin
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