| Histone deacetylases are dysregulated in rheumatoid arthritis and a novel HDAC3-selective inhibitor reduces IL-6 production by PBMC of RA patients. | |
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MedLine Citation:
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PMID: 21952924 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OBJECTIVES.: To demonstrate a role for histone deacetylase (HDAC) activity in rheumatoid arthritis (RA) and evaluate MI192, a novel HDAC3-selective inhibitor against a current non-selective HDAC inhibitor (HDI), Trichostatin A (TSA), for effects on proinflammatory cytokine production. METHODS.: HDAC and histone acetyltransferase (HAT) activity were measured in peripheral blood mononuclear cells (PBMC) from RA patients by spectrophotometric assays, prior to and 12 weeks following etanercept therapy. The effects of HDI treatment on cytokine production from both RA and healthy PBMC were assayed by ELISA. RESULTS.: RA PBMC had significantly increased HDAC activity (p=0.007) compared to healthy individuals, which was unaltered at 12 weeks post-etanercept therapy. TSA was a potent inhibitor of TNF, IFN-γ and IL-6 production from both RA and healthy PBMC. MI192 inhibited IFN-γ, TNF production at high concentrations and showed dose-dependent inhibition of IL-6 in RA PBMC but not healthy PBMC across a dose range of 10μM-5nM. CONCLUSION.: HDAC activity is dysregulated in RA PBMC and a potential target for therapeutic intervention, as it is not affected by conventional etanercept anti-TNF treatment. Both the selective (MI192) and non-selective (TSA) HDIs were found to regulate cytokine production from PBMC but their effects were cell type and compound specific. HDIs have therapeutic potential in RA, and HDAC-selective inhibition may improve therapeutic margins; however further clinical characterization is required to evaluate their biological safety. © 2011 American College of Rheumatology. |
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Authors:
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Justin Gillespie; Sinisa Savic; Chi Wong; Aiden Hempshall; Martyn Inman; Paul Emery; Ronald Grigg; Michael F McDermott |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-27 |
Journal Detail:
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Title: Arthritis and rheumatism Volume: - ISSN: 1529-0131 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0370605 Medline TA: Arthritis Rheum Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 by the American College of Rheumatology. |
Affiliation:
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NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Teaching Hospitals NHS Trust, LS9 7TF, UK; Leeds Institute of Molecular Medicine (LIMM), Wellcome Trust Brenner Building, University of Leeds, LS9 7TF, UK. |
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