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

Li, Jie; Xie, Hongfu; Wen, Ting; Liu, Hongbo; Zhu, Wu; Chen, Xiang

doi:10.3899/jrheum.090663

Cited by 70 publications

(63 citation statements)

References 38 publications

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“…We found that the HMGB1 content of circulating DNAcontaining ICs correlated positively with anti-dsDNA Ab production and disease activity and inversely with the level of serum complement 3 in SLE patients. Our data were consistent with previous studies that showed that the increased concentration of serum HMGB1 correlated positively with SLE disease activity and inversely with the levels of complement components C4 and C3 (47)(48)(49)(50). In addition, we found that miR-155 expression in PBMCs of SLE patients was significantly elevated and correlated positively with anti-dsDNA Ab production; this was in line with a previous study that showed that miR-155 was significantly increased in splenocytes from MRL-lpr mice or B6-lpr mice (51).…”

Section: Discussionsupporting

confidence: 93%

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

Wen

Lin

Chen

et al. 2013

The Journal of Immunology

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Anti-dsDNA Ab is reported to be the central pathogenic autoantibody involved in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms involved in anti-dsDNA Ab production remain unclear. Recent evidence indicated that DNA-containing immune complexes (ICs) in circulation (termed “circulating DNA-containing ICs”), which are one of the hallmarks of SLE, might be involved in autoantibody production. In this study, we explored their potential role in anti-dsDNA Ab production and the underlying mechanisms in patients with SLE. We demonstrated that circulating DNA-containing ICs were able to induce anti-dsDNA Ab. Of note, HMGB1 in circulating DNA-containing ICs was crucial for anti-dsDNA Ab induction. The HMGB1 content of circulating DNA-containing ICs also correlated positively with anti-dsDNA Ab production in patients with SLE. Further, we revealed that the TLR2/MyD88/microRNA-155 (miR-155) pathway was pivotal for HMGB1 to confer anti-dsDNA Ab induction, and Ets-1 was a functional target of miR-155 in the induction of anti-dsDNA Ab by circulating DNA-containing ICs. Finally, we validated the expression of miR-155 and Ets-1 and their correlation with anti-dsDNA Ab production in patients with SLE. To our knowledge, this is the first report of the crucial role of HMGB1 in autoantibody production mediated by the TLR2/MyD88/miR-155/Ets-1 pathway. These findings identify a novel mechanism to account for the persistent production of anti-dsDNA Ab in SLE and a clue for developing a novel therapeutic strategy against SLE.

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Section: Discussionsupporting

confidence: 93%

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

Wen

Lin

Chen

et al. 2013

The Journal of Immunology

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“…[16] Some studies have reported a relationship between the high serum level of HMGB1 and flare-ups of lupus disease activity. [17,18] All of these observations support the notion that the HMBG1-RAGE pathway plays a part in the pathogenesis of SLE.…”

supporting

confidence: 69%

“…[37] Studies have shown that the HMGB1 plasma level, one of the main RAGE ligands, is increased in the circulation of SLE, leading to the binding and consumption of sRAGE during the inflammatory process. [18,38] Another possible regulatory route of the sRAGE level is through alternative splicing and proteinases. Zong et al [39] recently proposed that sRAGE might not only function as a 'decoy' to exert its inhibitory effects on RAGE but also act in a more direct way by binding to the cell surface of RAGE to block the formation of homodimers.…”

Section: Discussionmentioning

confidence: 99%

A Soluble Receptor for Advanced Glycation End Product Levels in Patients with Systemic Lupus Erythematosus

2013

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Amaç: Bu çalışmada sistemik lupus eritematöz (SLE) olan hastalarda ileri glikasyon son ürünlerinin çözünür reseptörünün (sRAGE) plazma düzeyleri değerlendirildi ve bu düzeylerin farklı klinik, laboratuvar ve tedavi parametreleri ile olan ilişkisi araştırıldı. Hastalar ve yöntemler:Çalışmaya toplam 120 SLE hastası (111 kadın, 9 erkek) ve yaş ve cinsiyet eşleştirmeli 40 sağlıklı kontrol alındı. Plazma sRAGE düzeyleri, ticari olarak satılan enzim bağlı immünosorbent test (ELISA) kiti kullanılarak ölçüldü. Plazma sRAGE düzeyleri ve SLE'nin klinik ve laboratuvar özellikleri arasındaki muhtemel ilişki de değerlendirildi. Farklı tedavi yöntemlerinin sRAGE plazma düzeyleri üzerindeki etkinliği incelendi. Bulgular: Sağlıklı kontrollere kıyasla, SLE hastalarının plazma sRAGE düzeyleri anlamlı düzeyde daha düşüktü (p=0.003). Cilt döküntüsü veya serozit olan hastaların sRAGE düzeyleri, olmayanlara kıyasla anlamlı düzeyde daha yüksekti (sırasıyla p=0.036 ve p=0.017). Daha uzun süre tedavi edilen SLE hastalarının sRAGE düzeyleri, daha kısa süreli tedavi edilenlerden daha yüksekti (p=0.000). Kortikosteroid ile tedavi edilen ve kombine tedavi edilen hastalar arasında düzey açısından anlamlı bir fark yoktu (p=0.89). sRAGE düzeyleri ve total beyaz kan hücre (WBC) sayımı (r=-0.356; p=0.003), lenfosit (r=0.341; p<0.001) ve nötrofil (r=0.289; p=0.006) arasında anlamlı negatif bir ilişki vardı.Sonuç: Çalışmamızda SLE hastalarında sRAGE plazma düzeylerinin anlamlı derecede azaldığı bulundu. Bu da, sRAGE düzeylerinin hastalığın patogenezinde muhtemel bir rol oynadığını göstermektedir.Anahtar sözcükler: İleri glikasyon son ürünü; reseptör; sistemik lupus eritematöz. Objectives:In this study, we aimed to evaluate the plasma levels of a soluble receptor for advanced glycation end products (sRAGE) in patients with systemic lupus erythematosus (SLE) and to investigate their relationship with different clinical, laboratory, and therapeutic parameters. Patients and methods:A total of 120 patients with SLE (111 females, 9 males) and 40 age-and gender-matched healthy controls were included. The plasma sRAGE levels were measured using a commercially available enzyme-linked immunosorbent assay (ELISA). The possible relationship between plasma sRAGE levels with SLE clinical and laboratory characteristics were also assessed. The effectiveness of different therapeutic modalities on plasma sRAGE levels was analyzed. Results:The SLE patients had significantly lower plasma levels of sRAGE than the healthy controls (p=0.003). The patients with a skin rash or serositis had significantly higher sRAGE levels than those without (p=0.036 and p=0.017, respectively). The SLE patients who were treated over a longer period of time showed higher levels of sRAGE than those treated for shorter periods (p=0.000). No significant difference in levels was found among the patients treated with corticosteroids and those treated with combined therapy (p=0.89). There was a significant negative correlation between the sRAGE level and the total white blood cell (WBC) count (...

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“…In patients with renal involvement, higher HMGB1 levels were observed in serum compared with patients without renal involvement (50,52). In kidney biopsies of patients with lupus nephritis, cytoplasmic and extracellular HMGB1 was found (54,55), which was not present in control tissue.…”

Section: Hmgb1 and Lupus Nephritismentioning

confidence: 97%

Recent Developments in the Role of High-Mobility Group Box 1 in Systemic Lupus Erythematosus

Schaper

Westra

Bijl

2014

Mol Med

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High-mobility group box 1 (HMGB1) is an important molecule for several nuclear processes. Recently, HMGB1 has gained much attention as a damage-associated molecular pattern (DAMP) and has been implicated in the pathogenesis of several (auto)-immune diseases, in particular, systemic lupus erythematosus (SLE). A main pathogenic feature in SLE is the accumulation of apoptotic cells. Since HMGB1 is released from apoptotic cells it has been hypothesized that HMGB1 might fuel the inflammatory processes, as seen in this disease, and play a fundamental role in the pathogenesis. In this review, we discuss evidence in support of the theory that HMGB1 is an important mediator in SLE and may be considered a new autoantigen.

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

Abstract: 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.

Cited by 70 publications

References 38 publications

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

A Soluble Receptor for Advanced Glycation End Product Levels in Patients with Systemic Lupus Erythematosus

Recent Developments in the Role of High-Mobility Group Box 1 in Systemic Lupus Erythematosus

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