Histone deacetylase inhibitors MS-275 and SAHA induced growth arrest and suppressed lipopolysaccharide-stimulated NF-κB p65 nuclear accumulation in human rheumatoid arthritis synovial fibroblastic E11 cells

Methods. In this study, the anti-rheumatic mechanisms of MS-275 and SAHA were investigated in several cell culture models. Results. MS-275 and SAHA inhibited human RA synovial fibroblastic E11 cell proliferation in a non-cytotoxic manner. The anti-proliferative activities were associated with G(0)/G(1) phase arrest and induction of cyclin-dependent kinase inhibitor p21. In addition, MS-275 and SAHA suppressed lipopolysaccharide (LPS)-induced NF-kappa B p65 nuclear accumulation, IL-6, IL-18 and nitric oxide (NO) secretion as well as down-regulated pro-angiogenic VEGF and MMP-2 and MMP-9 production in E11 cells at sub-micromolar levels. At similar concentrations, MS-275 and SAHA suppressed LPS-induced NF-kappa B p65 nuclear accumulation and IL-1 beta, IL-6, IL-18 and TNF-alpha secretion in THP-1 monocytic cells. Moreover, NO secretion in RAW264.7 macrophage cells was also inhibited. Conclusions. In summary, MS-275 and SAHA exhibited their anti-rheumatic activities by growth arrest in RA synovial fibroblasts, inhibition of pro-inflammatory cytokines and NO, as well as down-regulation in angiogenesis and MMPs. Their anti-rheumatic activities may be mediated through induction of p21 and suppression of NF-kappa B nuclear accumulation.