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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.
Arthritis Rheum. 2012 Feb; 64(2):418-22.AR

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-γ (IFNγ) production in healthy PBMCs; IFNγ 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 μM-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.

Authors+Show Affiliations

University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21952924

Citation

Gillespie, Justin, et al. "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." Arthritis and Rheumatism, vol. 64, no. 2, 2012, pp. 418-22.
Gillespie J, Savic S, Wong C, et al. 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. Arthritis Rheum. 2012;64(2):418-22.
Gillespie, J., Savic, S., Wong, C., Hempshall, A., Inman, M., Emery, P., Grigg, R., & McDermott, M. F. (2012). 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. Arthritis and Rheumatism, 64(2), 418-22. https://doi.org/10.1002/art.33382
Gillespie J, et al. 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. Arthritis Rheum. 2012;64(2):418-22. PubMed PMID: 21952924.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Gillespie,Justin, AU - Savic,Sinisa, AU - Wong,Chi, AU - Hempshall,Aiden, AU - Inman,Martyn, AU - Emery,Paul, AU - Grigg,Ronald, AU - McDermott,Michael F, PY - 2011/9/29/entrez PY - 2011/9/29/pubmed PY - 2012/9/14/medline SP - 418 EP - 22 JF - Arthritis and rheumatism JO - Arthritis Rheum. VL - 64 IS - 2 N2 - 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-γ (IFNγ) production in healthy PBMCs; IFNγ 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 μM-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. SN - 1529-0131 UR - https://www.unboundmedicine.com/medline/citation/21952924/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_ L2 - https://doi.org/10.1002/art.33382 DB - PRIME DP - Unbound Medicine ER -