Abstract
BackgroundHistone deacetylase (HDAC) inhibitor has recently been reported to have a therapeutic effect as an anti-inflammatory agent in collagen-induced arthritis (CIA). We investigated the therapeutic effect of a new selective HDAC6 inhibitor, CKD-L, compared to ITF 2357 or Tubastatin A on CIA and regulatory T (Treg) cells in patients with rheumatoid arthritis (RA).MethodsCIA was induced by bovine type II collagen (CII) in DBA/1 J mice. Mice were treated with HDAC inhibitor for 18 days. Arthritis score was assessed and histological analysis was performed by hematoxylin and eosin (H&E) stain. Cytotoxic T-lymphocyte associated protein (CTLA)-4 expression in induced Treg cells was analyzed and suppression assay was analyzed using Treg cells and effector T (Teff) cells isolated from naive C57BL/6 mice by flow cytometry. Cytokines were analyzed in peripheral blood mononuclear cells (PBMC) of five patients with RA by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR). Tumor necrosis factor (TNF) was analyzed using PMA- activated THP-1 cells by ELISA. Suppression assay was analyzed using Treg cells and Teff cells isolated from RA patients by flow cytometry.ResultsIn the CIA model, CKD-L and Tubastatin A significantly decreased the arthritis score. CKD-L increased CTLA-4 expression in Foxp3+ T cells and inhibited the proliferation of Teff cells in the suppression assay. In RA PBMC, CKD-L significantly inhibited TNF and interleukin (IL)-1β, and increased IL-10. CKD-L and Tubastatin A inhibited TNF secretion from PMA-activated THP-1 cells. CKD-L and ITF 2357 inhibited the proliferation of Teff cells in RA patients in the suppression assay. Tubastatin A had no effect on inhibition of proliferation.ConclusionCKD-L decreased the arthritis score in CIA, reduced the expression of TNF and IL-1β, and increased the expression of IL-10 in PBMC from RA patients. CKD-L increased CTLA-4 expression and the suppressive function of Treg cells. These results suggest that CKD-L may have a beneficial effect in the treatment of RA.
Highlights
Histone deacetylase (HDAC) inhibitor has recently been reported to have a therapeutic effect as an anti-inflammatory agent in collagen-induced arthritis (CIA)
We investigated the therapeutic effect of the novel selective HDAC6 inhibitor, CKD-L, and compared its effect to those of the pan HDAC inhibitor, ITF 2357, and the selective HDAC6 inhibitor, Tubastatin A, in CIA, peripheral blood mononuclear cells (PBMC), and Treg cells from patients with rheumatoid arthritis (RA)
The arthritis scores of the mice treated with 30 mg/kg CKD-L tended to be lower than those of the mice treated with 15 mg/kg CKD-L
Summary
Histone deacetylase (HDAC) inhibitor has recently been reported to have a therapeutic effect as an anti-inflammatory agent in collagen-induced arthritis (CIA). Histone deacetylase (HDAC) and histone acetyltransferase (HAT) play important roles in the regulation of gene transcription [1]. In opposition to HAT, deacetylation of histone by HDAC represses gene transcription through chromatin condensation [5]. The class IV HDAC (HDAC11) shares structural similarities with both class I and class II HDACs. Class III HDACs (SirT 1–7) have distinct structures and different mechanisms of action. Class III HDACs (SirT 1–7) have distinct structures and different mechanisms of action Their enzymatic activity depends on the cofactor NAD+ [1, 6, 7]
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