Enhanced HMGB1 Expression May Contribute to Th17 Cells Activation in Rheumatoid Arthritis

Department of Immunology, Institute of Laboratory Medicine, Jiangsu University, Xuefu Road 301, Zhenjiang 212013, China.
Clinical and Developmental Immunology (Impact Factor: 2.93). 01/2012; 2012(1740-2522):295081. DOI: 10.1155/2012/295081
Source: PubMed


Rheumatoid arthritis(RA) is a common autoimmune disease associated with Th17 cells, but what about the effect of high-mobility group box chromosomal protein 1 (HMGB1) and the relationship between Th17-associated factors and HMGB1 in RA remains unknown. In the present study, we investigated the mRNA levels of HMGB1, RORγt, and IL-17 in peripheral blood mononuclear cells (PBMCs) from patients with rheumatoid arthritis by quantitative real-time PCR (RT-qPCR), and the concentrations of HMGB1, IL-17, and IL-23 in plasma were detected by ELISA. And then, the effect of HMGB1 on Th17 cells differentiation was analyzed in vitro. Our clinical studies showed that the mRNAs of HMGB1, RORγt, and IL-17 in patients were higher than that in health control (P < 0.05), especially in active RA patients (P < 0.05). The plasma HMGB1, IL-17, and IL-23 in RA patients were also higher than that in health control (P < 0.05); there was a positive correlation between the expression levels of HMGB1 and the amount of CRP, ERS, and RF in plasma. In vitro, the IL-17-produced CD4(+)T cells were increased with 100 ng/mL rHMGB1 for 12h, which indicated that the increased HMGB1 might contribute to Th17 cells activation in RA patients.

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    • "The prior study demonstrates that Th17 cells and their specific transcription factor or related cytokines are being recognized as important mediators in inflammatory and autoimmune diseases including RA [24]. To assess the relationships between the mRNA levels of PERP and IL-17 in RA patients, we first detected the IL-17 mRNA expression levels on PBMCs in healthy control, (HCs) and patients with RA, and then we examined the correlation between the mRNA levels of PERP and IL-17 in PBMCs of RA patients. "
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    ABSTRACT: Background: PERP, p53 apoptosis effector related to PMP-22, is a p53-dependent apoptosis in diverse cell types and has cell type-specific roles in p53-mediated apoptosis. However, its role in PBMCs of RA patients has remained largely unclear. Objectives: The aim of this study was to detect the expression levels of PERP on PBMCs of RA patients and healthy controls and analyze the role of PERP in the pathogenesis of RA. Methods. The mRNA expression levels of PERP and IL-17 were detected by real-time PCR in PBMCs from patients with RA (n = 40) and healthy controls (n = 40). The correlations of PERP expression levels to IL-17 transcripts and disease activity parameters were analyzed. Results: The PERP and IL-17 expression levels in the PBMCs were significantly decreased and increased in comparison of which in healthy controls. The mRNA expression levels of PERP in PBMCs from patients with RA were negatively correlated with IL-17 and disease activity parameters DAS28, RF, CRP, and ESR rather than Anti-CCP and ANA. Conclusions: These results demonstrated that PERP might be involved in the pathogenesis and a potential therapeutic target of RA by regulating the expression of IL-17.
    Full-text · Article · Aug 2013 · Clinical and Developmental Immunology
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    • "Furthermore, HMGB1 elicits increased suppressive capacity of Treg when co-cultured with effector T-cells in a RAGE-dependent fashion. Additionally, several reports provide evidence suggesting that HMGB1 may contribute to Th17 cells proliferation and activation in the context of autoimmune disease, including rheumatoid arthritis, myocarditis, as well as acute allograft rejection (Duan et al., 2011; Su et al., 2011; He et al., 2012b; Shi et al., 2012). "
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    ABSTRACT: High-mobility group box 1 (HMGB1) is a leaderless cytokine, like the IL-1 and FGF family members, that has primary roles within the nucleus and the cytosol. Within the nucleus, it serves as another guardian of the genome, protecting it from oxidant injury and promoting access to transcriptional complexes such as nuclear hormone/nuclear hormone receptors and p53/p73 complexes. Within the cytosol it promotes autophagy and recruitment of the myddosome to Toll-like receptor (TLR) 9 vesicular compartments. Outside of the cell, it can either bind to specific receptors itself, or with high affinity to DNA, nucleosomes, IL-1β, lipopolysaccharide, and lipoteichoic acid to mediate responses in specific physiological or pathological conditions. Currently identified receptors include TLR2, TLR4, the receptor for advanced glycation end products, CD24-Siglec G/10, chemokine CXC receptor 4, and TIM-3. In terms of its effects or functions within lymphoid cells, HMGB1 is principally secreted from mature dendritic cells (DCs) to promote T-cell and B-cell reactivity and expansion and from activated natural killer cells to promote DC maturation during the afferent immune response. Some studies suggest that its primary role in the setting of chronic inflammation is to promote immunosuppression. As such, HMGB1 is a central cytokine for all lymphoid cells playing a role complementary to its better studied role in myeloid cells.
    Full-text · Article · Mar 2013 · Frontiers in Immunology
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    Z He · S S Shotorbani · Z Jiao · Z Su · J Tong · Y Liu · P Shen · J Ma · J Gao · T Wang · S Xia · Q Shao · S Wang · H Xu
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    ABSTRACT: High-mobility group box 1 (HMGB1) is a non-histone nuclear protein that is released extracellulary and has been implicated in autoimmune disease. Toll-like receptor 2 (TLR2) signalling is thought to be essential for the inflammatory response and for immune disorders. In recent studies, enhanced HMGB1 and TLR2 expressions have been found in rheumatoid arthritis (RA), respectively. The aim of this study is to explore whether HMGB1 stimulation can up-regulate the expression of TLR2 on CD14(+) monocytes from patients with RA and to clarify the subsequent events involving Th17 cells and Th17 cell-associated cytokine changes. Our results showed that the frequency of CD14(+) cells in peripheral blood mononuclear cell (PBMC) was obviously increased, and enhanced expression of TLR2 on CD14(+) monocytes was also found in patients with RA, compared with healthy controls with statistical significance (P < 0.001). In addition, the levels of IL-17, IL-23 and IL-6 in supernatants from cultured monocytes from patients and in patient's plasma were increased, and NF-κB, the downstream target of TLR2, also showed a marked elevation after monocytes were stimulated by HMGB1. This implies that the enhanced TLR2 pathway and Th17 cell polarization may be due to HMGB1 stimulation in rheumatoid arthritis.
    Full-text · Article · Jul 2012 · Scandinavian Journal of Immunology
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