Expression of High Mobility Group Box Chromosomal Protein 1 and Its Modulating Effects on Downstream Cytokines in Systemic Lupus Erythematosus
ABSTRACT 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.
- SourceAvailable from: Hoiyda A Abdel Rasol
- "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). "
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- "Among the beneficial roles of the protein, it is to be mentioned also the promotion of tissue regeneration, realized by attracting stem cells and inducing their proliferation (Degryse et al., 2001). However, HMGB1 has been proposed to contribute to the pathogenesis of various chronic inflammatory and autoimmune diseases (Scaffidi et al., 2002; Palumbo et al., 2004; Wang et al., 2004; Pisetsky et al., 2008; Voll et al., 2008; Andersson & Harris, 2010), and high serum levels of HMGB1 have been found in several inflammatory events, including sepsis (Sunden-Cullberg et al., 2005), rheumatoid arthritis (Goldstein et al., 2007; Andersson & Harris, 2010), atherosclerosis (Li et al., 2006), chronic kidney disease (Bruchfeld et al., 2008), systemic lupus erythematosus (SLE) (Jiang & Pisetsky, 2008; Li et al., 2010; Urbonaviciute & Voll, 2011), as well as in cancer pathogenesis (Ellerman at al., 2007; Tang et al., 2010b). In particular, high expression of HMGB1 was observed in certain primary tumors including melanoma and colon, prostate, pancreatic , and breast cancers (Ellerman at al., 2007). "
ABSTRACT: HMGB1 (High-Mobility Group Box-1) is a nuclear protein that acts as an architectural chromatin-binding factor involved in the maintenance of nucleosome structure and regulation of gene transcription. It can be released into the extracellular milieu from immune and non-immune cells in response to various stimuli. Extracellular HMGB1 contributes to the pathogenesis of numerous chronic inflammatory and autoimmune diseases, including sepsis, rheumatoid arthritis, atherosclerosis, chronic kidney disease, systemic lupus erythematosus (SLE), as well as cancer pathogenesis. Interaction of released HMGB1 with the cell-surface receptor for advanced glycation end products (RAGE) is one of the main signalling pathways triggering these diseases. It has been also demonstrated that the inhibition of the HMGB1-RAGE interaction represents a promising approach for the modulation of the inflammatory and tumour-facilitating activity of HMGB1. In this review we describe various approaches recently proposed in the literature to inhibit HMGB1 and the related inflammatory processes, especially focusing on the block of RAGE-HMGB1 signalling. Several strategies are based on molecules which mainly interact with RAGE as competitive antagonists of HMGB1. As an alternative, encouraging results have been obtained with HMGB1-targeting, leading to the identification of compounds that directly bind to HMGB1, ranging from small natural or synthetic molecules, such as glycyrrhizin and gabexate mesilate, to HMGB1-specific antibodies, peptides, proteins as well as bent DNA-based duplexes. Future perspectives are discussed in the light of the overall body of knowledge acquired by a large number of research groups operating in different but related fields.Pharmacology [?] Therapeutics 11/2013; 141(3). DOI:10.1016/j.pharmthera.2013.11.001 · 7.75 Impact Factor
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ABSTRACT: A key question in immunology concerns how sterile injury activates innate immunity to mediate damaging inflammation in the absence of foreign invaders. The discovery that HMGB1, a ubiquitous nuclear protein, mediates the activation of innate immune responses led directly to the understanding that HMGB1 plays a critical role at the intersection of the host inflammatory response to sterile and infectious threat. HMGB1 is actively released by stimulation of the innate immune system with exogenous pathogen-derived molecules and is passively released by ischemia or cell injury in the absence of invasion. Established molecular mechanisms of HMGB1 binding and signaling through TLR4 reveal signaling pathways that mediate cytokine release and tissue damage. Experimental strategies that selectively target HMGB1 and TLR4 effectively reverse and prevent activation of innate immunity and significantly attenuate damage in diverse models of sterile and infection-induced threat.Annual Review of Immunology 04/2010; 29(1):139-62. DOI:10.1146/annurev-immunol-030409-101323 · 41.39 Impact Factor