Date: Monday, November 9, 2015
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Epigenetic changes including histone modification play an important role in development of rheumatoid arthritis (RA). Histone deacetylase inhibitor (HDACi) increases transcription of numerous genes by rendering chromatin state more accessible for transcription factor and RNA-polymerase, leading to anti-proliferative and anti-inflammatory effects. In addition, direct change in acetylation state of cellular proteins may alter cellular function.
This study was aimed to investigate the effects of CKD-H059, a novel HDAC-6 inhibitor, on regulatory T (Treg) cells and fibroblast-like-synoviocytes (FLS) of RA patients in vitro and on development of arthritis in vivo.
Methods: Regulatory T cells (iTreg) were induced from naïve CD4+ T cells of RA patients. CSFE labeled effector T cells (Teff) from healthy subjects were co-cultured with iTreg in the increasing concentrations of CKD-H059 and Teff proliferation was analyzed by flow cytometry. After 24 hour activation with IL-1β in the increasing concentrations of CKD-H059, proliferation and IL-6 production of RA-FLS were assessed. Cytoplasmic acetylation of α-tubulin in the activated RA-FLS was visualized by confocal microscopy. Adjuvant-induced arthritis (AIA) was induced in mice that were treated with oral CKD-H059 (3, 10, 30, 50, 100 mg/kg) and the severity of arthritis was assessed on 9, 13, and 16 days.
Results: In the presence of CKD-H059, iTreg efficiently inhibited the proliferation of Teff in a dose dependent manner. CKD-H059 induced acetylation of α-tubulin in cytoskeleton with subsequent cell morphology change (i.e. from long spindle form into round flat cells) and inhibited cell proliferation and production of pro-inflammatory cytokine IL-6. In AIA mice, oral CKD-H059 was able to prevent the development of clinical arthritis in a dose-dependent manner.
Conclusion: The novel HDAC6 inhibitor CKD-H059 inhibits the inflammatory response in T cells and FLS of RA in vitro and ameliorates arthritis severity in vivo. Therefore, CKD-H059 might offer a novel treatment option for RA.
To cite this abstract in AMA style:Jang YJ, Oh BR, Lim H, Bae D, Ha N, Choi YI, Park JK, Lee EY, Lee EB, Song YW. A Novel Histone Deacetylase 6 Inhibitor, CKD-H059 Inhibits the Inflammatory Response in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/a-novel-histone-deacetylase-6-inhibitor-ckd-h059-inhibits-the-inflammatory-response-in-rheumatoid-arthritis/. Accessed January 27, 2020.
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