HMGB1 Levels Are Increased in Patients with Juvenile Idiopathic Arthritis, Correlate with Early Onset of Disease, and Are Independent of Disease Duration

Schierbeck, Hanna; Pullerits, Rille; Pruunsild, Chris; Fischer, M; Holzinger, Dirk; Laestadius, Åsa; Sundberg, Erik; Harris, Helena Erlandsson

doi:10.3899/jrheum.120987

Cited by 47 publications

(43 citation statements)

References 30 publications

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“…We also analyzed levels of additional inflammatory mediators, including MCP-1, IP-10, RANTES, IL-6, and IL-8. Confirming our previously reported results, no correlation was recorded with total HMGB1 levels (data not included) (35). In addition, no correlation was noted with any traces of HMGB1 PTMs (data not included).…”

Section: Lundbä Ck Et Alsupporting

confidence: 85%

“…In addition, intra-articular HMGB1 injections induce destructive arthritis in mice and antibodies targeting HMGB1 ameliorate disease activity in several models of arthritis (16,30,34). We have recently reported increased levels of HMGB1 in SF of juvenile idiopathic arthritis ( JIA) patients (35). However, measurement of total HMGB1 levels without distinguishing between the different redox isoforms does not adequately reveal the functional contribution of HMGB1 to the studied inflammatory condition, nor whether the increased HMGB1 levels reflect increased cell death or activation of inflammatory cells.…”

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confidence: 99%

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Characterization of the Inflammatory Properties of Actively Released HMGB1 in Juvenile Idiopathic Arthritis

Lundbäck

Stridh

Klevenvall

et al. 2016

Antioxidants & Redox Signaling

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Aims: Pathogenic effects of the endogenous inflammatory mediator high mobility group box protein 1 (HMGB1) have been described in several inflammatory diseases. Recent reports have underlined the importance of post-translational modifications (PTMs) in determination of HMGB1 function and release mechanisms. We investigated the occurrence of PTMs of HMGB1 obtained from synovial fluid (SF) of juvenile idiopathic arthritis ( JIA) patients. Results: Analyses of 17 JIA patients confirmed high HMGB1 levels in SF. Liquid chromatography tandem mass-spectrometry (LC-MS/MS) analyses of PTMs revealed that total HMGB1 levels were not associated with increased lactate dehydrogenase activity but strongly correlated with nuclear location sequence 2 (NLS2) hyperacetylation, indicating active release of HMGB1. The correlation between total HMGB1 levels and NLS2 hypoacetylation suggests additional, acetylation-independent release mechanisms. Monomethylation of lysine 43 (K43), a proposed neutrophil-specific PTM, was strongly associated with high HMGB1 levels, implying that neutrophils are a source of released HMGB1. Analysis of cysteine redox isoforms, fully reduced HMGB1, disulfide HMGB1, and oxidized HMGB1, revealed that HMGB1 acts as both a chemotactic and a cytokine-inducing mediator. These properties were associated with actively released HMGB1. Innovation: This is the first report that characterizes HMGB1-specific PTMs during a chronic inflammatory condition. Conclusion: HMGB1 in SF from JIA patients is actively released through both acetylation-dependent and -nondependent manners. The presence of various functional HMGB1 redox isoforms confirms the complexity of their pathogenic role during chronic inflammation. Defining HMGB1 release pathways and redox isoforms is critical for the understanding of the contribution of HMGB1 during inflammatory processes. Antioxid. Redox Signal. 24, 605-619.

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Section: Lundbä Ck Et Alsupporting

confidence: 85%

mentioning

confidence: 99%

Characterization of the Inflammatory Properties of Actively Released HMGB1 in Juvenile Idiopathic Arthritis

Lundbäck

Stridh

Klevenvall

et al. 2016

Antioxidants & Redox Signaling

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“…Melinda Magna 1 and David S Pisetsky of characteristic tissue pathology (for example, arthritis) or functional disturbance (for example, muscle weakness in myositis) by HMGB1 in in vitro or in vivo models; and (d) effectiveness of agents directed at HMGB1 in animal models (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Table 1 lists diseases in which studies implicate a role of HMGB1 in pathogenesis.…”

Section: The Role Of Hmgb1 In the Pathogenesis Of Inflammatory And Aumentioning

confidence: 99%

The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases

Magna

Pisetsky

2014

Mol Med

287

199

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High-mobility group box 1 (HMGB1) protein is a highly abundant protein that can promote the pathogenesis of inflammatory and autoimmune diseases once it is in an extracellular location. This translocation can occur with immune cell activation as well as cell death, with the conditions for release associated with the expression of different isoforms. These isoforms result from posttranslational modifications, with the redox states of three cysteines at positions 23, 45 and 106 critical for activity. Depending on the redox states of these residues, HMGB1 can induce cytokine production via toll-like receptor 4 (TLR4) or promote chemotaxis by binding the chemokine CXCL12 for stimulation via CXCR4. Fully oxidized HMGB1 is inactive. During the course of inflammatory disease, HMGB1 can therefore play a dynamic role depending on its redox state. As a mechanism to generate alarmins, cell death is an important source of HMGB1, although each major cell death form (necrosis, apoptosis, pyroptosis and NETosis) can lead to different isoforms of HMGB1 and variable levels of association of HMGB1 with nucleosomes. The association of HMGB1 with nucleosomes may contribute to the pathogenesis of systemic lupus erythematosus by producing nuclear material whose immunological properties are enhanced by the presence of an alarmin. Since HMGB1 levels in blood or tissue are elevated in many inflammatory and autoimmune diseases, this molecule can serve as a unique biomarker as well as represent a target of novel therapies to block its various activities.

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“…Second, .................................................................................................................. (#)P < 0.05, showed a significant difference compared with corresponding siRNA control group. (*)P < 0.05, showed a significant difference compared with corresponding oxLDL-treated group; (&)P < 0.05, showed a significant difference compared with corresponding oxLDL-treated þ90 mM hypaconitine group besides vascular disease, many inflammatory diseases are also induced by the relocation and release of HMGB1, 19,20 so the hypaconitine in regulation of the HDAC3-HMGB1 pathway may provide a new anti-inflammatory therapy. Third, A. carmichaelii is a commonly used Chinese herb in clinic.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase-high mobility group box-1 pathway targeted by hypaconitine suppresses the apoptosis of endothelial cells

Bai

et al. 2017

Exp Biol Med (Maywood)

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First, our study shows the antiapoptosis effect of Aconitum carmichaelii and its active component hypaconitine on endothelial cells. It may provide new strategies for the treatment of diseases involving endothelium damage. Second, this finding indicates the function of hypaconitine in regulating HDAC3-HMGB1 pathway, which suggests a new anti-inflammatory therapy. Third, due to its poisonousness, A. carmichaelii is always used with caution in clinics. Thus, the identification of hypaconitine as an active component of A. carmichaelii could contribute to the development of toxicity-decreasing procedure for A. carmichaelii. AbstractHypaconitine is an active component of Aconitum carmichaelii Debx, a Chinese medicinal herb for the treatment of cardiovascular diseases, but the mechanism underlying its effect remains elusive. In this study, we found that hypaconitine, rather than aconitum alkaloids in A. carmichaelii (e.g. aconitine, mesaconitine and benzoylaconitine), prevented endothelial cells from damage due to oxidized low-density lipoprotein (oxLDL) challenge. Cleaved caspase 3 expression in endothelial cells was up-regulated by oxLDL and markedly attenuated by hypaconitine, suggesting that hypaconitine inhibited the oxLDL-induced cell apoptosis. Microarray analysis revealed that histone deacetylase 3 (HDAC3) was significantly increased by hypaconitine. The cytoplasmic relocation and extracellular release of high-mobility group box 1 (HMGB1, an HDAC3 downstream effector) in endothelial cells were significantly increased by oxLDL and markedly decreased by hypaconitine. The effect of hypaconitine on the oxLDL-induced apoptosis and HMGB1 release in endothelial cells was significantly reduced by the suppression of HDAC3 by siRNA or a specific inhibitor. Thus, this study proves that the histone deacetylase-HMGB1 pathway targeted by hypaconitine suppresses the apoptosis of endothelial cells. Our findings are of therapeutic significance and provide the potential of hypaconitine exploitation.

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HMGB1 Levels Are Increased in Patients with Juvenile Idiopathic Arthritis, Correlate with Early Onset of Disease, and Are Independent of Disease Duration

Cited by 47 publications

References 30 publications

Characterization of the Inflammatory Properties of Actively Released HMGB1 in Juvenile Idiopathic Arthritis

Characterization of the Inflammatory Properties of Actively Released HMGB1 in Juvenile Idiopathic Arthritis

The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases

Histone deacetylase-high mobility group box-1 pathway targeted by hypaconitine suppresses the apoptosis of endothelial cells

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