Histone Deacetylase Inhibitors Suppress Inflammatory Activation of Rheumatoid Arthritis Patient Synovial Macrophages and Tissue

Grabiec, Aleksander M; Krausz, Sarah; Jager, Wilco de; Burakowski, Tomasz; Groot, Dion; Sanders, ME; Prakken, Berent J.; Maśliński, Włodzimierz; Eldering, Eric; Tak, Paul P.; Reedquist, Kris A.

doi:10.4049/jimmunol.0901467

Cited by 203 publications

(161 citation statements)

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“…In summary, our data showing that SIRT1 contributes to the activation of human synovial cells by promoting the pro-inflammatory, proliferative and potentially adhesive properties of RASF suggest an adverse function of SIRT1 in the pathogenesis of RA and are in line with previous reports in human cells [13,14]. In mice, however, SIRT1 was shown to have the opposite effects, since deletion of SIRT1 aggravated the inflammatory arthritis in serum transfer arthritis model and increased production of pro-inflammatory cytokines in murine macrophages [16].…”

Section: Discussionsupporting

confidence: 79%

“…Down regulation of SIRT1 or inhibition of sirtuin activities in synovial cells of RA patients was found to reduce the expression of inflammatory mediators [13,14], and overexpression of SIRT1 increased production of pro-inflammatory cytokines in rheumatoid arthritis synovial fibroblasts (RASF) and monocytes from healthy persons [13]. In contrast, levels of SIRT1 were diminished in joint tissues of mice with collagen-induced arthritis [15].…”

Section: Introductionmentioning

confidence: 99%

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Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

et al. 2015

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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. The function of sirtuin (SIRT)1 in RA is inconclusive. In human synovial cells, SIRT1 was shown to promote cytokine production and apoptosis resistance. However, deletion of SIRT1 aggravated inflammatory arthritis in mice and increased production of pro-inflammatory cytokines in murine macrophages. In the current study, we investigated the regulation, expression, and function of SIRT1 in RA, in particular its role in adhesion and proliferation of human RA synovial fibroblasts (RASF). We found that expression of SIRT1 was increased in vivo in synovial tissues of RA smokers and in vitro by stimulation of RASF with TNF, but decreased upon treatment with cigarette smoke extract. Synovial tissues of RA smokers showed higher leukocytic infiltration that positively correlated with enhanced levels of SIRT1. Global transcriptome analysis revealed that SIRT1 modulates expression of genes involved in the regulation of inflammatory response and cell adhesion. In functional studies, silencing of SIRT1 reduced proliferation and leukocytic adhesion to RASF but showed inconsistent results in the regulation of adhesion to plastic. In conclusion, SIRT1 modulates the proliferative and potentially also adhesive properties of RASF and can therefore promote progression of RA. KEY MESSAGES: SIRT1 is upregulated by TNF but decreased upon CSE treatment of RASF. Upregulation of SIRT1 in RA smokers correlates with increased leukocytic infiltration. SIRT1 modulates expression of genes regulating cell adhesion and inflammation. SIRT1 regulates proliferation of RASF. AbstractRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. The function of sirtuin (SIRT)1 in RA is inconclusive. In human synovial cells SIRT1 was shown to promote cytokine production and apoptosis resistance. However, deletion of SIRT1 aggravated inflammatory arthritis in mice and increased production of pro-inflammatory cytokines in murine macrophages. In the current study we investigated the regulation, expression and function of SIRT1 in RA, in particular its role in adhesion and proliferation of human RA synovial fibroblasts (RASF). We found that expression of SIRT1 was increased in vivo in synovial tissues of RA smokers and in vitro by stimulation of RASF with TNFα, but decreased upon treatment with cigarette smoke extract.Synovial tissues of RA smokers showed higher leukocytic infiltration that positively correlated with enhanced levels of SIRT1. Global transcriptome analysis revealed that SIRT1modulates expression of genes involved in the regulation of inflammatory response and cell adhesion. In functional studies, silencing of SIRT1 reduced proliferation and leukocytic adhesion to RASF, but showed inconsistent results in the regulation of adhesion to plastic. In conclusion, SIRT1 modulates the proliferative and potentially also adhesive properties of RASF and can t...

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

et al. 2015

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“…There is increasing evidence that HDA inhibitors may also exhibit antiinflammatory properties (3). ITF2357 (recently named givinostat) is a hydroxamic acid containing an HDA inhibitor, which reduces the production and release of several proinflammatory cytokines (tumor necrosis factor ␣, interleukin-1␤ [⌱L-1␤], interferon-␥, IL-6, and IL-12) from human blood monocytes (4) as well as in models of autoimmune diseases and inflammation, including models of arthritis and synovial cell functions (5,6).…”

mentioning

confidence: 99%

Safety and efficacy of an oral histone deacetylase inhibitor in systemic‐onset juvenile idiopathic arthritis

Vojinović¹,

Damjanov²,

D’Urzo³

et al. 2011

Arthritis & Rheumatism

190

117

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Objective. The current treatment options for systemic-onset juvenile idiopathic arthritis (JIA) are methotrexate, steroids, and biologic agents. This study was undertaken to evaluate the safety of the orally active histone deacetylase inhibitor givinostat (ITF2357) and its ability to affect the disease.Methods. Givinostat was administered orally, for up to 12 weeks at a dosage of 1.5 mg/kg/day, to 17 patients with systemic-onset JIA who had had active disease for >1 month. Disease activity was clinically assessed using the American College of Rheumatology Pediatric 30 (ACR Pedi 30), ACR Pedi 50, or ACR Pedi 70 criteria for improvement and a systemic feature score. The primary goal was safety and the primary efficacy end point was the number of patients completing 12 weeks of treatment who were responders.Results. Givinostat was safe and well tolerated, with adverse events (AEs) being mild or moderate, of short duration, and self-limited. The 17 patients from the intent-to-treat population reported a total of 44 AEs, and the 9 patients in the per-protocol population reported a total of 25. Six AEs in 3 patients (nausea, vomiting, and fatigue) were related to the study drug, but each resolved spontaneously and no patient was withdrawn from the study due to drug-related AEs. In the per-protocol population at week 4, the improvement as measured by the ACR Pedi 30, ACR Pedi 50, and ACR Pedi 70, respectively, was 77.8%, 55.6%, and 22.2%, and this increased further to 77.8%, 77.8%, and 66.7% at week 12. The most consistent finding was the reduction in the number of joints with active disease or with limited range of motion.Conclusion. After 12 weeks, givinostat exhibited significant therapeutic benefit in patients with systemiconset JIA, particularly with regard to the arthritic component of the disease, and showed an excellent safety profile.Histone deacetylases (HDAs) are intracellular enzymes that maintain nucleosome histones in a state of deacetylation so that DNA remains tightly bound and inaccessible to transcription factors. Inhibition of HDAs results in hyperacetylation of histones, which allows for the sufficient unraveling of DNA for binding transcription factors and the synthesis of messenger RNA (1,2). There is increasing evidence that HDA inhibitors may also exhibit antiinflammatory properties (3). ITF2357 (recently named givinostat) is a hydroxamic acid containing an HDA inhibitor, which reduces the production and release of several proinflammatory cytokines (tumor necrosis factor ␣, interleukin-1␤ [⌱L-1␤], interferon-␥, IL-6, and IL-12) from human blood monocytes (4) as well as in models of autoimmune diseases and inflammation, including models of arthritis and synovial cell functions (5,6).Systemic-onset juvenile idiopathic arthritis (JIA) is an example of combined autoinflammatory and autoimmune disease. Reduction of the painful and destructive arthritis component of the disease remains a goal that has still not been achieved even with anticytokine parenteral therapies (7,8). The primary objective of t...

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“…Also, in vitro treatment of RA macrophages and synovial explants showed potent anti-inflammatory actions of HDAC inhibitors [30]. The mechanisms by which HDAC inhibitors promote anti-inflammatory effects are not completely understood, but could stem from enhanced acetylation of histones at the promoters of transcriptional repressors, enhanced transcription of anti-inflammatory gene products, or modification of non-histone targets [31].…”

Section: Histone Modifications In Ramentioning

confidence: 99%