Therapeutic effect of a novel histone deacetylase 6 inhibitor, CKD-L, on collagen-induced arthritis in vivo and regulatory T cells in rheumatoid arthritis in vitro

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.

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

“…RA may involve defects in acetylation (212), reflected in the beneficial activity of a histone deacetylase inhibitor in CIA (213). It is also likely that there are changes in DNA methylation (214)(215)(216)(217) as has been noted in regulatory T cells (218) and synovial fibroblasts (219).…”

Targeted inhibition of histone deacetylase 6 in inflammatory diseases

“…Treatment with small molecular inhibitors of HDAC6 has been shown to reduce the production of the pro‐inflammatory cytokines, IL‐6, TNF‐α, and IL‐1β, and successfully ameliorate synovial inflammation, suggesting a potential role for these drugs in the treatment of RA. For example, in the collagen‐induced arthritis mouse models and in RA patients, the HDAC6‐selective inhibitor, CKD‐L, inhibits IL‐6, TNF‐α, and IL‐1β expression, and increases IL‐10 production, resulting in a decrease in the arthritis score and inhibition of the proliferation of effector T cells . Similarly, tubastatin A, another HDAC6 inhibitor, has been shown to successfully ameliorate synovial inflammation and protect against joint destruction in collagen antibody‐induced arthritis mice.…”

“…For example, in the collagen-induced arthritis mouse models and in RA patients, the HDAC6-selective inhibitor, CKD-L, inhibits IL-6, TNF-α, and IL-1β expression, and increases IL-10 production, resulting in a decrease in the arthritis score and inhibition of the proliferation of effector T cells. 63 Similarly, tubastatin A, another HDAC6 inhibitor, has been shown to successfully ameliorate synovial inflammation and protect against joint destruction in collagen antibody-induced arthritis mice. These results suggest that HDAC6-selective inhibitors may have antiinflammatory effects in RA (Table 1).…”

Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis

“…The in ammatory environment of RA transforms normal resident synoviocytes into tissue-destructive FLS, which produce large amounts of IL-6, IL-8, and extracellular matrix proteinases MMP-1 and MMP-3 [30,31]. CKD-506 markedly inhibits joint-destructive FLS [18,29]. The multicellular effects of HDAC6 inhibition by CKD-506 might contribute to the anti-arthritic effects observed in the murine RA model; these effects were comparable with those of tofacitinib, a JAK/STAT signaling inhibitor with proven clinical e cacy (Figure 4).…”

“…HDAC6 is different from other HDAC isotypes in that it is present almost exclusively in the cytosol and, therefore, is not involved in epigenetic regulation [15,16]. Overexpression of HDAC6 is associated with increased in ammatory responses [17], and inhibiting it reduces disease activity in murine model of RA and systemic lupus erythematosus [18,19]. CKD-506 is a potent and selective HDAC6 inhibitor (>100 fold selectivity for HDAC6 over other HDAC isotypes).…”