4.3 Article

A Novel HDAC1-Selective Inhibitor Attenuates Autoimmune Arthritis by Inhibiting Inflammatory Cytokine Production

Journal

BIOLOGICAL & PHARMACEUTICAL BULLETIN
Volume 45, Issue 9, Pages 1364-1372

Publisher

PHARMACEUTICAL SOC JAPAN

Keywords

histone deacetylase 1 inhibitor; rheumatoid arthritis; collagen-induced arthritis; collagen anti-body-induced arthritis; macrophage; T helper 17 cell

Funding

  1. AMED-Crest [21gm1310009h0002]
  2. Japan Society for the Promotion of Science [20H00509, 20H05876, JP20K07552, JP17K15734]
  3. Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research (DT)
  4. SECOM Science and Technology Foundation
  5. Uehara Memorial Foundation
  6. Asahi Grass Foundation
  7. Keio University

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This study evaluated the therapeutic effect of a novel selective HDAC1 inhibitor TTA03-107 in arthritis models and found that it can attenuate the severity of autoimmune arthritis. The results demonstrate that TTA03-107 can slow down the development of arthritis by inhibiting the differentiation and activation of macrophages and Th17 cells.
Rheumatoid arthritis (RA) is systemic autoimmune arthritis that causes joint inflammation and destruction. Accumulating evidence has shown that inhibitors of class I histone deacetylases (HDACs) (i.e., HDAC1, 2, 3, and 8) are potential therapeutic candidates as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). Nevertheless, the inhibition of class I HDACs has severe adverse effects because of their broad spectrum. We evaluated the therapeutic effect of a novel selective HDAC1 inhibitor TTA03-107 for collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models in mice. We also examined the effect of TTA03-107 in bone marrow- derived macrophages (BMDMs) and T helper 17 (Th17) cells in vitro. Here, we delineate that TTA03-107 reduced the severity of autoimmune arthritis without obvious adverse effects in CIA and CAIA models. Moreover, TTA03-107 suppressed the production of inflammatory cytokines, such as interleukin (IL)-1 beta, tumor necrosis factor (TNF)-a, and IL-17A, in serum and joint tissue. In vitro treatment of BMDMs with TTA03-107 dampened the M1 differentiation and inflammatory cytokine production. TTA03-107 also suppressed the differentiation of Th17 cells. These results demonstrate that TTA03-107 can attenuate the development of arthritis in experimental RA models by inhibiting the differentiation and activation of macrophages and Th17 cells. Therefore, TTA03-107 is a potential tsDMARD candidate.

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