HMGB1 was originally identified as a DNA-binding protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be "passively released" into the extracellular milieu by necrotic and damaged somatic cells. Extracellular HMGB1 represents an optimal "necrotic marker" selected by the innate immune system to recognize tissue damage and initiate reparative responses. HMGB1 in the extracellular milieu promotes maturation of myeloid and plasmacytoid dendritic cells, and induces myocardial regeneration after infarction. However, extracellular HMGB1 also acts as a potent pro-inflammatory cytokine that contributes to the pathogenesis of diverse inflammatory and infectious disorders. A growing number of studies indicate that HMGB1 is a successful therapeutic target in experimental models of ischemia/reperfusion, acute respiratory distress syndrome, rheumatoid arthritis, sepsis, and cancer. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses while preventing its pathological potential. This article focus on the immuno-regulatory role of HMGB1 and its contribution to infectious and inflammatory disorders.
"On the other hand, inflammatory cells, including monocytes, macrophages , and dendritic cells, during apoptosis actively secrete hyperacetylated form of HMGB1, which induces immunological tolerance (Kazama et al, 2008). Thus, HMGB1 has diverse effects on immunity acting as a pro-inflammatory cytokine, enhancing both innate and adaptive immune responses that contribute to the pathogenesis of various disorders, from sepsis and autoimmunity to cancer (Ulloa and Messmer, 2006). Overexpression of HMGB1, as well as cytoplasmic localization, has been observed in various human carcinomas (Flohr et al, 2001; Kuniyasu et al, 2003; Wu et al, 2008), including HNSCC (Liu et al, 2010; Wild et al, 2012) and OSCC (Sasahira et al, 2008; Ahn et al, 2012). "
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The current study examined the single nucleotide polymorphisms (SNPs) in High Mobility Group Box 1 (HMGB1) gene in patients with Oral Squamous Cell Carcinoma (OSCC) and Oral Lichen Planus (OLP).Materials and methodsThe study was conducted on 93 OSCC patients, 53 OLP patients, and 100 controls, all Caucasians of the same ethnicity, matched by age. HMGB1 genotypes for 4 SNPs, 2262G/A (rs1045411), 1177G/C (rs3742305), 3814C/G (rs2249825), and rs4540927, were assessed using TaqMan SNP Genotyping Assays, Applied Biosystems.ResultsThe HMGB1 1177GG genotype was associated with lymph-node metastasis and tumor stage in OSCCs (p=0.016 and p=0.030, respectively). Genotype 1177GG resulted in poorer recurrence-free survival (RFS), p=0.000. The 1177G/C polymorphism was an independent predictor of RFS compared to GG genotype, p=0.001. The three polymorphisms were in linkage disequilibrium (LD). The AGC and GGC haplotypes were associated with an increased oral cancer risk, determined over the Haplotype Odds Ratios, (HOR=13.316, p=0.015, and HOR=5.769, p=0.029, respectively). The AGC haplotype was related to erosive OLP progression to OSCC (HOR=12.179, p=0.001).ConclusionsHMGB1 polymorphism 1177G/C could be associated with tumor progression and recurrence-free survival in OSCC patients. The haplotypes of HMGB1 gene might be associated with susceptibility to OSCC and OLP progression to OSCC.This article is protected by copyright. All rights reserved.
"High-mobility group box 1 (HMGB1) is a chromatin protein that is released from necrotic cells or activated immune cells . Extracellular HMGB1 is capable of interacting with RAGE or Toll-like receptor and activating a pro-inflammatory cascade . It has recently been shown that HMGB1 is up-regulated in COPD lung tissue and co-localised with RAGE . "
[Show abstract][Hide abstract] ABSTRACT: The receptor for advanced glycation end-products (RAGE) is highly expressed in the lung, where it is believed to have a homeostatic role. Reduced plasma levels of soluble RAGE (sRAGE) have been reported in patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to evaluate the association of plasma sRAGE levels with a longitudinal decline of lung function. We have also measured plasma levels of high mobility group box 1 (HMGB1), a RAGE ligand which has been associated with chronic inflammatory diseases including COPD.
Baseline plasma concentrations of sRAGE and HMGB1 were measured in non-smokers (n = 32), smokers without COPD (n = 212), and smokers with COPD (n = 51), and the associations of the plasma sRAGE and HMGB1 levels with longitudinal declines of lung function during a 4-year follow-up period were analysed.
The plasma levels of sRAGE were significantly lower in smokers without COPD and in smokers with COPD, as compared to those of non-smokers. Plasma sRAGE levels positively correlated with FVC and FEV1 and inversely correlated with BMI and pack-years. Lower sRAGE levels were associated with greater declines of FEV1/FVC over 4 years in all participants. Moreover, multivariate regression analysis indicated that the baseline plasma sRAGE concentration was an independent predictor of FEV1/FVC decline in all groups. A subgroup analysis showed that decreased sRAGE levels are significantly associated with a more rapid decline of FEV1/FVC in smokers with COPD. There was no significant correlation between plasma HMGB1 levels and longitudinal decline of lung function.
Lower plasma concentrations of sRAGE were associated with greater progression of airflow limitations over time, especially in smokers with COPD, suggesting that RAGE might have a protective role in the lung.
BMC Pulmonary Medicine 04/2014; 14(1):68. DOI:10.1186/1471-2466-14-68 · 2.40 Impact Factor
"1-d-fasting induced cytoplasmic translocations of the protein, with particularly strong staining in sinusoid-associated KCs (Fig. 2C). Cytoplasmic localization is associated with either HMGB1 secretion or with the autophagic response to starvation  . Since HMGB1 release (i.e., circulating levels) was reduced after 1-d-fasting, we examined an involvement of autophagy. "
[Show abstract][Hide abstract] ABSTRACT: Fasting and calorie restriction are associated with a prolonged life span and an increased resistance to stress. The protective effects of fasting have been exploited for the mitigation of ischemic organ injury, yet the underlying mechanisms remain incompletely understood. Here, we investigated whether fasting protects liver against ischemia reperfusion (IR) through energy-preserving or anti-inflammatory mechanisms.
Fasted C57BL6 mice were subjected to partial hepatic IR. Injury was assessed by liver enzymes and histology. Raw 264-7 macrophage-like cells were investigated in vitro. Sirt1 and Hmgb1 were inhibited using Ex527 and neutralizing antibodies, respectively.
Fasting for one, but not two or three days, protected from hepatic IR injury. None of the investigated energy parameters correlated with the protective effects. Instead, inflammatory responses were dampened in one-day-fasted mice and in starved macrophages. Fasting alone led to a reduction in circulating Hmgb1 associated with cytoplasmic Hmgb1 translocation, aggregate formation and autophagy. Inhibition of autophagy re-elevated circulating Hmgb1 and abolished protection in fasted mice, as did supplementation with Hmgb1. In vitro, Sirt1 inhibition prevented Hmgb1 translocation, leading to elevated Hmgb1 in the supernatant. In vivo, Sirt1 inhibition abrogated the fasting-induced protection, but had no effect in the presence of neutralizing Hmgb1 antibody.
Fasting for one day protects from hepatic IR injury via Sirt1-dependent downregulation of circulating Hmgb1. The reduction in serum Hmgb1 appears to be mediated by its engagement in the autophagic response. These findings integrate Sirt1, Hmgb1 and autophagy into a common framework that underlies the anti-inflammatory properties of short-term fasting.
Journal of Hepatology 04/2014; 61(2). DOI:10.1016/j.jhep.2014.04.010 · 11.34 Impact Factor
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