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High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts
Heidi W?h?maa, Hanna Schierbeck, Hulda S Hreggvidsdottir, Karin Palmblad, Anne-Charlotte Aveberger, Ulf Andersson, Helena Harris
Arthritis Research & Therapy , 2011, DOI: 10.1186/ar3450
Abstract: Synovial fibroblasts obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients were stimulated with HMGB1 alone or in complex with LPS, IL-1α or IL-1β. Tumour necrosis factor (TNF) production was determined by enzyme-linked immunospot assay (ELISPOT) assessment. Levels of IL-10, IL-1-β, IL-6 and IL-8 were measured using Cytokine Bead Array and matrix metalloproteinase (MMP) 3 production was determined by ELISA.Stimulation with HMGB1 in complex with LPS, IL-1α or IL-1β enhanced production of TNF, IL-6 and IL-8. HMGB1 in complex with IL-1β increased MMP production from both RASF and OASF. The cytokine production was inhibited by specific receptor blockade using detoxified LPS or IL-1 receptor antagonist, indicating that the synergistic effects were mediated through the partner ligand-reciprocal receptors TLR4 and IL-1RI, respectively.HMGB1 in complex with LPS, IL-1α or IL-1β boosted proinflammatory cytokine- and MMP production in synovial fibroblasts from RA and OA patients. A mechanism for the pathogenic role of HMGB1 in arthritis could thus be through enhancement of inflammatory and destructive mechanisms induced by other proinflammatory mediators present in the arthritic joint.The highly conserved protein high mobility group box protein 1 (HMGB1) exerts vital functions in the nucleus of all eukaryotic cells. When tissue injury is inflicted and inflammation is induced, HMGB1 can be released extracellularly and can then convey inflammatory functions. Extracellular HMGB1 may induce cytokine production, up-regulation of adhesion molecules on endothelial cells and activation of dendritic cells and T cells [1-11]. The reported presence of extracellular HMGB1 in multiple inflammatory conditions and the beneficial effects of HMGB1 blockade in preclinical models of inflammatory diseases have thus led to the acknowledgement of HMGB1 as an inflammatory mediator with pathogenic functions in several inflammatory diseases (reviewed in [12]).HMGB1 interacts with th
The role of high mobility group box chromosomal protein 1 expression in the differential diagnosis of hepatic actinomycosis: a case report
Wu Chuan-Xin,Guo Hui,Gong Jian-Ping,Liu Qi
Journal of Medical Case Reports , 2013, DOI: 10.1186/1752-1947-7-31
Abstract: Introduction Primary hepatic actinomycosis is a rare disease, but is important in the differential diagnosis of hepatoma in endemic areas. As high mobility group box chromosomal protein 1 plays an important role in the pathogenesis of both acute and chronic inflammatory conditions, we postulate that high mobility group box chromosomal protein 1 may have a possible pathogenic role in hepatic actinomycosis. To the best of our knowledge, our report is the first to detect an association between highly elevated high mobility group box chromosomal protein 1 expression and hepatic actinomycosis. Case presentation A 67-year-old Chinese man was admitted to our hospital with a three-month history of epigastric pain, anorexia, and subjective weight loss. Ultrasonography and computed tomography of the patient’s abdomen confirmed a hypodense mass measuring seven cm in diameter in the left lateral segment of his liver. A hepatic tumor was suspected and surgical resection was scheduled. Histopathologic examination revealed that the overall features of the hepatic tissues were consistent with hepatic actinomycosis. Whole blood and hepatic tissue samples of the patient, of patients who had hepatocellular carcinoma and of healthy donors were collected. Serum high mobility group box chromosomal protein 1 concentration in actinomycosis was 8.5ng/mL, which was higher than the hepatocellular carcinoma level of 5.2ng/mL and the normal level of Conclusion High mobility group box chromosomal protein 1 may have a potent biological effect on the pathogenesis of hepatic actinomycosis as a novel cytokine and may be a useful marker in the differential diagnosis of hepatic actinomycosis.
Microglial Amyloid- 1-40 Phagocytosis Dysfunction Is Caused by High-Mobility Group Box Protein-1: Implications for the Pathological Progression of Alzheimer's Disease  [PDF]
Kazuyuki Takata,Tetsuya Takada,Aina Ito,Mayo Asai,Manami Tawa,Yuki Saito,Eishi Ashihara,Hidekazu Tomimoto,Yoshihisa Kitamura,Shun Shimohama
International Journal of Alzheimer's Disease , 2012, DOI: 10.1155/2012/685739
Abstract: In Alzheimer disease (AD) patient brains, the accumulation of amyloid- (A ) peptides is associated with activated microglia. A is derived from the amyloid precursor protein; two major forms of A , that is, A 1-40 (A 40) and A 1-42 (A 42), exist. We previously reported that rat microglia phagocytose A 42, and high mobility group box protein 1 (HMGB1), a chromosomal protein, inhibits phagocytosis. In the present study, we investigated the effects of exogenous HMGB1 on rat microglial A 40 phagocytosis. In the presence of exogenous HMGB1, A 40 markedly increased in microglial cytoplasm, and the reduction of extracellular A 40 was inhibited. During this period, HMGB1 was colocalized with A 40 in the cytoplasm. Furthermore, exogenous HMGB1 inhibited the degradation of A 40 induced by the rat microglial cytosolic fraction. Thus, extracellular HMGB1 may internalize with A 40 in the microglial cytoplasm and inhibit A 40 degradation by microglia. This may subsequently delay A 40 clearance. We further confirmed that in AD brains, the parts of senile plaques surrounded by activated microglia are composed of A 40, and extracellular HMGB1 is deposited on these plaques. Taken together, microglial A phagocytosis dysfunction may be caused by HMGB1 that accumulates extracellularly on A plaques, and it may be critically involved in the pathological progression of AD. 1. Introduction Alzheimer’s disease (AD) is characterized by the deposition of amyloid- (A ) plaques, accumulation of neurofibrillary tangles (NFTs), and loss of synapses and neurons in particular brain areas [1]. Experimental studies using transgenic AD mouse models have demonstrated that A accelerates NFT formation [2, 3] and is closely associated with synaptic damage [4]. In contrast, A reduction in the brain by A immunization restores cognitive functions in transgenic AD mouse models [5–9] and also appears to slow cognitive decline in human AD patients [10]. Thus, the accumulation of A may play a key role in the pathogenesis of AD [11]. A is derived from the sequential proteolysis of amyloid precursor protein (APP) by - and γ-secretases and is composed of 37–43 amino acid residues because γ-secretase, which is a protein complex including presenilin (PS), generates the C-terminal of A with different lengths [12]. Among the variations in A , A 1-40 (A 40) and A 1-42 (A 42) are the major species found in AD brains. The most predominant species deposited in A plaques is A 42 [13], which is prone to aggregation [14] and indicates increased neurotoxicity [15]. On the other hand, A 40 is the major soluble
Unraveling the role of high mobility group box protein 1 in severe trauma
Edward Abraham
Critical Care , 2009, DOI: 10.1186/cc8141
Abstract: High mobility group box protein 1 (HMGB1) has long been known to participate as a nuclear cofactor in the regulation of transcriptional events. However, over the past several years, HMGB1 has been demonstrated to be secreted by cells, such as macrophages, activated by lipopolysaccharide and other mediators associated with sepsis and acute inflammatory processes. A study that now appears in Critical Care not only shows that plasma HMGB1 levels are elevated within less than an hour after severe trauma but also reports an association between HMGB1 levels and severity of injury and survival [1]. These results are consistent with those previously reported in which serum concentrations of HMGB1 were found to be increased within 1 hour of severe trauma, but did not correspond with outcome [2]. The differences in the relationship between outcome and circulating HMGB1 concentrations reported in the two studies are likely to reflect the much larger patient population enrolled by Cohen and colleagues [1], especially as multiple reports from patients with severe sepsis also have found that higher HMGB1 levels in the period immediately after hospitalization were associated with worse clinical outcome [3,4].Initial studies suggested that HMGB1 acted as a pro-inflammatory mediator and was capable of contributing to organ system dysfunction and mortality in animal models of sepsis [5,6]. However, recent experiments using highly purified HMGB1 have brought into question the ability of HMGB1 to activate cells and directly participate in acute inflammatory conditions [7,8]. Rather, HMGB1 appears to potentiate inflammatory responses through avidly binding to pro-inflammatory mediators, including lipopolysaccharide, inter-leukin-1, and DNA [7,9]. The lack of endogenous inflammatory activity of HMGB1 itself in cell culture experiments is consistent with the finding that high circulating levels of HMGB1 are present in patients who are clinically recovering from severe infection, such as p
High mobility group box 1 as a mediator of endotoxin administration after hemorrhagic shock-primed lung injury
Guo, F.;Shi, Y.;Xu, H.;Ding, J.;
Brazilian Journal of Medical and Biological Research , 2009, DOI: 10.1590/S0100-879X2009005000009
Abstract: high mobility group box 1 (hmgb1) was discovered as a novel late-acting cytokine that contributes to acute lung injury (ali). however, the contribution of hmgb1 to two-hit-induced ali has not been investigated. to examine the participation of hmgb1 in the pathogenesis of ali caused by the two-hit hypothesis, endotoxin was injected intratracheally in a hemorrhagic shock-primed ali mouse model. concentrations of hmgb1 in the lung of the shock group were markedly increased at 16 h (1.63 ± 0.05, compared to the control group: 1.02 ± 0.03; p < 0.05), with the highest concentration being observed at 24 h. in the sham/lipopolysaccharide group, lung hmgb1 concentrations were found to be markedly increased at 24 h (1.98 ± 0.08, compared to the control group: 1.07 ± 0.03; p < 0.05). administration of lipopolysaccharide to the hemorrhagic shock group resulted in a notable hmgb1 increase by 4 h, with a further increase by 16 h. intratracheal lipopolysaccharide injection after hemorrhagic shock resulted in the highest lung leak at 16 h (2.68 ± 0.08, compared to the control group: 1.05 ± 0.04; p < 0.05). compared to the hemorrhagic shock/lipopolysaccharide mice, blockade of hmgb1 at the same time as lipopolysaccharide injection prevented significantly pulmonary tumor necrosis factor-alpha, interleukin-1beta and myeloperoxidase. lung leak was also markedly reduced at 16 h; blockade of hmgb1 24 h after lipopolysaccharide injection failed to alter lung leak or myeloperoxidase at 48 h. our observations suggest that hmgb1 plays a key role as a late mediator when lipopolysaccharide is injected after hemorrhagic shock-primed ali and the kinetics of its release differs from that of one-hit ali. the therapeutic window to suppress hmgb1 activity should not be delayed to 24 h after the disease onset.
High mobility group box-1 protein – one step closer to the clinic?
Tom Mollnes
Critical Care , 2008, DOI: 10.1186/cc6944
Abstract: In the previous issue of Critical Care, Kornblit and coworkers [1] presented novel data on a possible relation between polymorphisms in the HMGB1 gene (which encodes the high mobility group box [HMGB]1 protein) and clinical outcome in patients with systemic inflammatory response syndrome. Specifically, they identified significant associations between a promoter variant (-1377delA) and overall late survival and between an exon 4 variant (982C>T) and early mortality due to infection. The latter was also associated with several clinical parameters related to disease severity. These data are of particular interest in the light of recent research suggesting a pathogenetic role for HMGB1 in experimental sepsis.Definite strengths of the study are the reliable gene technology methods they used, the prospective design of the study, and the authors' experience in handling genetic data in complex clinical settings. However, clinical studies will always be hampered by a risk for inaccurate diagnosis, despite the existence of diagnostic criteria. This is particularly true in patients who have a complex disease pattern and in disorders such as systemic inflammatory response syndrome, which have a number of underlying causes. Thus, the data presented must be confirmed in larger studies and by other groups before they can be used clinically to inform efforts to predict outcome or select patients for specific treatments.HMGB1 is constitutively expressed in the nuclei of eukaryotic cells. It belongs to a family of high mobility group nuclear proteins that were described in the 1970s as gene regulators that bind to and change the configuration of DNA [2,3]. It later became evident that HMGB1 is actively secreted from cells, has cytokine activities and is a late mediator of endotoxin lethality in mice [4]. Passive release of HMGB1 from necrotic cells also triggers inflammation [5]. Receptors for HMGB1 signalling include RAGE (receptor for advanced glycation end-products) and Toll-like
The Protective Effect of Lidocaine on Septic Rats via the Inhibition of High Mobility Group Box 1 Expression and NF- B Activation  [PDF]
Huan-Liang Wang,Yan-Qiu Xing,Ying-Xue Xu,Fei Rong,Wei-Fu Lei,Wen-Hua Zhang
Mediators of Inflammation , 2013, DOI: 10.1155/2013/570370
Abstract: Lidocaine, a common local anesthetic drug, has anti-inflammatory effects. It has demonstrated a protective effect in mice from septic peritonitis. However, it is unknown whether lidocaine has effects on high mobility group box 1 (HMGB1), a key mediator of inflammation. In this study, we investigated the effect of lidocaine treatment on serum HMGB1 level and HMGB1 expression in liver, lungs, kidneys, and ileum in septic rats induced by cecal ligation and puncture (CLP). We found that acute organ injury induced by CLP was mitigated by lidocaine treatment and organ function was significantly improved. The data also demonstrated that lidocaine treatment raised the survival of septic rats. Furthermore, lidocaine suppressed the level of serum HMGB1, the expression of HMGB1, and the activation of NF-κB p65 in liver, kidneys, lungs, and ileum. Taken together, these results suggest that lidocaine treatment exerts its protective effection on CLP-induced septic rats. The mechanism was relative to the inhibitory effect of lidocaine on the mRNA expression level of HMGB1 in multiple organs, release of HMGB1 to plasma, and activation of NF-κB. 1. Introduction Sepsis, a systemic inflammatory response syndrome that complicates infection and injury, results in the excessive stimulation on the host immune system and the production of various proinflammatory cytokines. The overproduction of cytokines leads to lethal multiple organ damage [1]. High mobility group box 1 (HMGB1), a nuclear protein widely studied as a transcription factor and growth factor, has recently been identified as a critical mediator of severe sepsis [2, 3]. In addition to its nuclear expression, HMGB1 can be released from inflammatory cells and necrotic tissues during endotoxemia and sepsis [4]. Excessive HMGB1 release has been found to play a key role in the pathogenesis of acute and chronic inflammation. Serum HMGB1 was significantly elevated from 8 to 72?h after endotoxin exposure [2, 3], in comparison with the early mediators, TNF-α and IL-1β. The treatment with the delayed administration of anti-HMGB1 antibodies [2, 3], a box of HMGB1 [3], and ethyl pyruvate [5] (an inhibitor of HMGB1) beginning as late as the disappearance of plasma TNF-α and IL-1β significantly increases survival. On the other hand, HMGB1 binds to cell surface receptors once released from the nucleus, and the nuclear factor (NF)-κB signaling pathway may be activated [6]. Thus, the therapeutic window for anti-HMGB1 therapies is significantly wider than that of TNF-α targeted interventions, and it may now be possible to develop
High Mobility Group Box Protein-1 in Wound Repair  [PDF]
Elia Ranzato,Simona Martinotti,Marco Pedrazzi,Mauro Patrone
Cells , 2012, DOI: 10.3390/cells1040699
Abstract: High-mobility group box 1 protein (HMGB1), a member of highly conserved non-histone DNA binding protein family, has been studied as transcription factor and growth factor. Secreted extracellularly by activated monocytes and macrophages or passively released by necrotic or damaged cells, extracellular HMGB1 is a potent mediator of inflammation. Extracellular HMGB1 has apparently contrasting biological actions: it sustains inflammation (with the possible establishment of autoimmunity or of self-maintaining tissue damage), but it also activates and recruits stem cells, boosting tissue repair. Here, we focus on the role of HMGB1 in physiological and pathological responses, the mechanisms by which it contributes to tissue repair and therapeutic strategies base on targeting HMGB1.
Activation of Peroxisome Proliferator-Activated Receptor by Rosiglitazone Inhibits Lipopolysaccharide-Induced Release of High Mobility Group Box 1  [PDF]
Jung Seok Hwang,Eun Sil Kang,Sun Ah Ham,Taesik Yoo,Hanna Lee,Kyung Shin Paek,Chankyu Park,Jin-Hoi Kim,Dae-Seog Lim,Han Geuk Seo
Mediators of Inflammation , 2012, DOI: 10.1155/2012/352807
Abstract: Peroxisome proliferator-activated receptors (PPARs) are shown to modulate the pathological status of sepsis by regulating the release of high mobility group box 1 (HMGB1), a well-known late proinflammatory mediator of sepsis. Ligand-activated PPARs markedly inhibited lipopolysaccharide- (LPS) induced release of HMGB1 in RAW 264.7 cells. Among the ligands of PPAR, the effect of rosiglitazone, a specific ligand for PPAR , was superior in the inhibition of HMGB1 release induced by LPS. This effect was observed in cells that received rosiglitazone before LPS or after LPS treatment, indicating that rosiglitazone is effective in both treatment and prevention. Ablation of PPAR with small interfering RNA or GW9662-mediated inhibition of PPAR abolished the effect of rosiglitazone on HMGB1 release. Furthermore, the overexpression of PPAR markedly potentiated the inhibitory effect of rosiglitazone on HMGB1 release. In addition, rosiglitazone inhibited LPS-induced expression of Toll-like receptor 4 signal molecules, suggesting a possible mechanism by which rosiglitazone modulates HMGB1 release. Notably, the administration of rosiglitazone to mice improved survival rates in an LPS-induced animal model of endotoxemia, where reduced levels of circulating HMGB1 were demonstrated. Taken together, these results suggest that PPARs play an important role in the cellular response to inflammation by inhibiting HMGB1 release. 1. Introduction High mobility group box 1 (HMGB1) is a highly conserved nonhistone nuclear protein that exhibits diverse functions according to its cellular location. In the intracellular compartment, it participates in a number of fundamental cellular processes such as transcription, replication, and DNA repair [1]. In addition to its intracellular functions, extracellular HMGB1 plays an important role in inflammatory responses when actively secreted from stressed cells [2]. Proinflammatory properties of HMGB1 as a crucial cytokine were first documented in a report demonstrating that HMGB1 is actively secreted by activated macrophages, serving as a late mediator of lethality in a mouse model of sepsis [3]. Furthermore, circulating HMGB1 levels were elevated with delayed fashion in the mouse model and in patients with sepsis characterized by overwhelming inflammatory and immune responses, leading to tissue damage, multiple-organ failure and death [3–5]. Recent reports indicated that HMGB1 is a late mediator of sepsis, acting as a key regulator in acute and chronic inflammation [2, 3]. In fact, the administration of anti-HMGB1 antibodies or inhibitors,
Evaluation of high mobility group box 1 protein as a presurgical diagnostic marker reflecting the severity of acute appendicitis  [cached]
Wu Chuanxin,Sun Hang,Wang Hongliang,Chi Junmeng
Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine , 2012, DOI: 10.1186/1757-7241-20-61
Abstract: Objectives To validate the role of high mobility group box-1(HMGB1) in diagnosis of acute appendicitis (AA) with different pathological severity. Methods According to the pathologically diagnosis, 150 patients underwent appendectomies between Jan. 2007 and Dec, 2010 were divided into acute simple, acute suppurative and acute gangrenous appendicitis as group 1, 2 and 3, respectively. Each patient group contains 50 sex and age matched cases to make comparison with 50 healthy volunteers. The mRNA and protein expression levels of serum HMGB1 were determined by real-time quantitative PCR and enzyme linked immunosorbent assay (ELISA). Serum High-sensitivity C-reactive protein (hs-CRP) levels were determined by rate nephelometric immunoassay. Results In comparison with health volunteers, relative HMGB1 mRNA levels in group 1, 2 and 3 were significantly increased 3.05 ± 0.51,8.33 ± 0.75 and 13.74 ± 1.09 folds, reflecting a tendency of augmented severity. In accordance, serum protein levels of HMGB1 were 10.97 ± 1.64, 14.42 ± 1.56 and 18.08 ± 2.41 ng/ml in 3 patient groups, which are significantly higher than that of healthy volunteers’ 5.47 ± 0.73 ng/ml. hs-CRP levels were 12.85 ± 3.41, 21.04 ± 1.98 and 31.07 ± 5.46 ng/ml in 3 patients groups compared with 2.06 ± 0.77 ng/ml in controls. The concentrations of HMGB1 and hs-CRP were both positively correlated with disease severity. Conclusion Serum HMGB1 constitutes as a valuable marker in diagnosis of AA. Positively correlated with hs-CRP level, mRNA and protein expression of HMGB1 to a certain extent reflected the severity of AA.
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