Expression of High Mobility Group Box Chromosomal Protein 1 and Its Modulating Effects on Downstream Cytokines in Systemic Lupus Erythematosus

Department of Dermatology, Xiangya Hospital, Central South University, Hunan, China.
The Journal of Rheumatology (Impact Factor: 3.19). 04/2010; 37(4):766-75. DOI: 10.3899/jrheum.090663
Source: PubMed


To compare the expression of high mobility group box chromosomal protein 1 (HMGB1) and the modulating effects on its downstream cytokines in patients with systemic lupus erythematosus (SLE) and healthy controls.
HMGB1 concentrations in serum from SLE patients and controls were measured by immunoblot analysis. HMGB1 messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMC) was detected by real-time reverse transcription-polymerase chain reaction. Immunofluorescence assay was employed to examine the translocation of HMGB1 in monocytes after endotoxin stimulation. Release of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) by PBMC after rHMGB1 stimulation was also measured.
Serum HMGB1 levels and HMGB1 mRNA expressions in PBMC were elevated in SLE patients compared with controls. A positive correlation was demonstrated between HMGB1 concentrations and SLE Disease Activity Index. There was an inverse correlation between HMGB1 levels and C4 and C3 concentrations in SLE patients. HMGB1 concentrations were higher in patients with vasculitis and myositis. Lipopolysaccharide stimulated a temporarily elevated release of HMGB1 in SLE patients compared with controls. The pattern and localization of HMGB1 staining in monocytes were similar in both groups. After stimulation with rHMGB1, TNF-alpha level decreased but IL-6 level increased in SLE patients compared with controls.
Our findings suggest that increased serum levels of HMGB1 in SLE may be associated with lupus disease activity. The altered production of TNF-alpha and IL-6 in response to rHMGB1 stimulation may participate in the disruption of cytokine homeostasis in SLE.

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    • "Proinflammatory and immune-stimulatory function of HMGB1 indicate its association with autoimmune diseases including rheumatoid arthritis and SLE [29] [31]. Furthermore, HMGB1 has been found to be significantly elevated in lupus sera and identified as one of the components in DNA-containing immune complexes that enhance proinflammatory cytokine production [32]. All these data indicate that HMGB1 might act as a new inflammation-related factor in SLE; however, the precise role of HMGB1 in the inflammatory response during the pathogenesis of SLE still remains unclear. "
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    ABSTRACT: Background/Purpose. HMGB1, which may act as a proinflammatory mediator, has been proposed to contribute to the pathogenesis of multiple chronic inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE); however, the precise mechanism of HMGB1 in the pathogenic process of SLE remains obscure. Method. The expression of HMGB1 was measured by ELISA and western blot. The ELISA was also applied to detect proinflammatory cytokines levels. Furthermore, nephritic pathology was evaluated by H&E staining of renal tissues. Results. In this study, we found that HMGB1 levels were significantly increased and correlated with SLE disease activity in both clinical patients and murine model. Furthermore, gain- and loss-of-function analysis showed that HMGB1 exacerbated the severity of SLE. Of note, the HMGB1 levels were found to be associated with the levels of proinflammatory cytokines such as TNF-α and IL-6 in SLE patients. Further study demonstrated that increased HMGB1 expression deteriorated the severity of SLE via enhancing macrophage inflammatory response. Moreover, we found that receptor of advanced glycation end products played a critical role in HMGB1-mediated macrophage inflammatory response. Conclusion. These findings suggested that HMGB1 might be a risk factor for SLE, and manipulation of HMGB1 signaling might provide a therapeutic strategy for SLE.
    Full-text · Article · Jun 2015 · Journal of Immunology Research
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    • "In SLE, HMGB1 was demonstrated to be associated with nucleosomes released from apoptotic cells and to contribute to the immunostimulatory effect of nucleosomes (Urbonaviciute et al. 2008). In addition, HMGB1 has been found to be significantly elevated in lupus sera and has been regarded as one of the components in DNA-containing immune complexes that enhance cytokine production (Li et al. 2010). "

    Full-text · Article · Jan 2015
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    • "Previous studies have shown that high mobility group box 1 (HMGB1) protein, as the class of "alarmins", participates in the innate and adaptive immune responses such as chronic obstructive pulmonary disease (COPD), asthma, sepsis, cystic fibrosis (CF) and systemic lupus erythematosus 5-9. There is evidence that the release of damage associated molecular patterns (DAMPs) in the epithelium, such as HMGB1, may evoke inflammatory responses in the lower airways and local nasal mucosa 10-12. "
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    ABSTRACT: Chronic rhinosinusitis with nasal polyps is a common disease with still unclear pathophysiologic mechanisms. The airway epithelial barrier has been shown to be involved in different chronic disorders, including rhinitis, nasal polyposis and asthma. High mobility group box 1 (HMGB1), a primarily nuclear protein, is involved in the induction of airway inflammation in patients with chronic rhinosinusitis, allergy, asthma and COPD. Pathogen-derived lipopolysaccharide is widely used as a trigger for inflammation. However, the molecular dialogue between LPS and HMGB1 in the delayed inflammatory processes remains to be explored, and the regulation of HMGB1 release through LPS from epithelial cells has not been extensively studied in patients with chronic rhinosinusitis and nasal polyps. The objective of the present study was to investigate the relocation of HMGB1 in LPS-induced human nasal epithelial cells in vitro. We obtained epithelial cells of nasal polyps from 10 patients requiring surgery for sinusitis at the ENT Department of the Chinese PLA General Hospital. The primary cultured human nasal epithelial (HNE) cells were stimulated with LPS. The expression and translocation of HMGB1 in intracellular and culture supernatants were determined using Western blot and immunofluorescence assay. HMGB1 protein was released in a time-dependent fashion in culture supernatants: in fact, expression of HMGB1 protein in HNE cells showed no significant changes at 0-24 h after exposure to 100 μg/ml LPS, but increased significantly at 48 and 72 hr. Immunofluorescence analysis revealed the transfer of HMGB1 from nuclei to cytoplasm in response to LPS exposure after 24 hr. These data reveal a hitherto unrecognized association between HMGB1 and LPS in human nasal epithelial cells. LPS can affect HMGB1 translocation and release, suggesting the involvement of HMGB1, through inflammatory mediators, in chronic rhinosinusitis with nasal polyps.
    Full-text · Article · Dec 2013 · Acta otorhinolaryngologica Italica: organo ufficiale della Società italiana di otorinolaringologia e chirurgia cervico-facciale
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