Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3–selective inhibitor reduces interleukin‐6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients

Abstract

Objective. To characterize the role of histone deacetylase (HDAC) activity in rheumatoid arthritis (RA) and to evaluate the effects of MI192, a novel HDAC-3-selective inhibitor, compared with the established nonselective HDAC inhibitor trichostatin A (TSA), on proinflammatory cytokine production.Methods. Activity of HDAC and histone acetyltransferase was measured in peripheral blood mononuclear cells (PBMCs) from RA patients by spectrophotometric assay, prior to and after 12 weeks of etanercept therapy. The effects of HDAC inhibitor treatment on cytokine production in both RA and healthy PBMCs were assessed by enzyme-linked immunosorbent assay.Results. RA PBMCs exhibited significantly increased HDAC activity (P ‫؍‬ 0.007) compared to PBMCs from healthy individuals, and the increase was unaltered after 12 weeks of etanercept therapy. TSA was a potent inhibitor of tumor necrosis factor (TNF) and interleukin-6 (IL-6) production in both RA and healthy PBMCs and of interferon-␥ (IFN␥) production in healthy PBMCs; IFN␥ was not produced by RA PBMCs. MI192 inhibited TNF production at high concentrations and dose-dependently inhibited IL-6 in RA PBMCs but not healthy PBMCs, across a dose range of 10 M-5 nM.Conclusion. HDAC activity is dysregulated in RA PBMCs and is a potential target for therapeutic intervention, as it is not affected by conventional anti-TNF treatment with etanercept. Both the selective and the nonselective HDAC inhibitors (MI192 and TSA, respectively) were found to regulate cytokine production from PBMCs, but their effects were cell type and compound specific. HDAC inhibitors have potential in the treatment of RA, and HDAC-selective inhibition may improve the therapeutic margin of safety; however, further clinical characterization and evaluation for adverse effects is needed.

Epigenetics in rheumatoid arthritis

“…Different HDAC inhibitors (Table 1), which mostly target several members of HDAC, were described to have beneficial effects in vitro and in vivo in RA [17,[25][26][27][28][29][30][31]. However, many of the observed effects of HDAC inhibitors were shown to be chromatin-independent and nonepigenetic (reviewed in [17]).…”

Gene expression signature-based approach identifies a pro-resolving mechanism of action for histone deacetylase inhibitors

“…The selective FPR2 antagonist WRW 4 was purchased from Calbiochem, Nottingham, UK. The PKC inhibitor (PKC [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] ) and the protein phosphatase 2 inhibitor (okadaic acid) were purchased from Tocris Bioscience, Bristol, UK.…”

“…[16][17][18] Using the gene expression profile produced by the antiinflammatory pro-resolving molecule annexin A1 (AnxA1), 19 we found very strong positive connections with several members of the histone deacetylase inhibitors (HDACIs) class of drugs. HDACIs are being actively investigated for the treatment of cancer owing to their pro-apoptotic effect, 20,21 although a substantial body of evidence indicates that this chemically-unrelated family of molecules affords potent anti-inflammatory properties 22,23 with potential therapeutic in pathologies including rheumatoid arthritis, 24,25 inflammatory bowel disease 26 and heart disease. 27,28 The mechanisms underlying these anti-inflammatory properties of HDACIs are largely not understood.…”

Histone deacetylases (HDAC) in physiological and pathological bone remodelling

“…The fact that HDACi are a new class of drugs that might help combat the ongoing bone damage associated with RA, has prompted a number of in vitro and in vivo RA related studies [7,[21][22][23][99][100][101]. The first study to assess effects of HDACi using an animal model of inflammatory arthritis was reported in 2003 [85].…”