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Therapeutic effects of CKD-H059, a novel histone deacetylase 6 inhibitor, in rheumatoid arthritis

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Authors
장유진
Advisor
송영욱
Major
융합과학기술대학원 분자의학 및 바이오제약학과
Issue Date
2016-02
Publisher
서울대학교 융합과학기술대학원
Keywords
RAHDAC inhibitorCKD-H059PBMCTreg cellsFLS
Description
학위논문 (석사)-- 서울대학교 융합과학기술대학원 : 융합과학기술대학원 분자의학 및 바이오제약학과, 2016. 2. 송영욱.
Abstract
Background: Epigenetic changes including histone modification may play a role in development of rheumatoid arthritis (RA). Histone deacetylase inhibitor (HDACi) could increase transcription of numerous genes by rendering chromatin state more accessible for transcription factor and RNA-polymerase, leading to anti-proliferative and anti-inflammatory effects.
Objective: This study was aimed to investigate the effects of CKD-H059, a novel HDAC-6 inhibitor, on peripheral blood mononuclear cells (PBMCs), regulatory T (Treg) cells and fibroblast-like-synoviocytes (FLSs) of RA patients in vitro and on development of arthritis in animal model.
Methods: After 24 hours activation with LPS in the increasing concentrations of CKD-H059, TNF-α, IL-1β, IL-6 and IL-10 production of RA PBMC were assessed. Regulatory T cells (iTreg) were induced from naive CD4+ T cells of RA patients. CFSE 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 activation with IL-1β in the increasing concentrations of CKD-H059, MMP-1, MMP-3, IL-6 and IL-8 production of RA-FLS were assessed. Cytoplasmic acetylation of α-tubulin in the activated RA-FLS was visualized by confocal microscopy. Rats with adjuvant-induced arthritis (AIA) were treated with oral CKD-H059 (3, 10, 30, 50, 100 mg/kg) once a day and the severity of arthritis was assessed on 9, 13, and 16 days.
Result: CKD-H059 decreased TNF-α and increased IL-10 of RA PBMCs without impact on cell viability. In the presence of CKD-H059, iTreg efficiently inhibited the proliferation of Teff in a dose dependent manner. CKD-H059 inhibited MMP-1, MMP-3, IL-6 and IL-8 and induced acetylation of α-tubulin in cytoskeleton with subsequent cell morphology change. In AIA rat, 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 PBMCs and FLS of RA and restores Treg cell function. CKD-H059 ameliorates arthritis severity in animal model. Therefore, CKD-H059 might offer a novel treatment option for RA.
Language
English
URI
http://hdl.handle.net/10371/133393
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Molecular Medicine & Biopharmaceutical Sciences(분자의학 및 바이오제약학과)Theses (Master's Degree_분자의학 및 바이오제약학과)
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