Therapeutic effects and its mechanism of HDACi on Arthritis

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Histone deacetylases(HDACs) remove an acetyl group from lysine residue of histones and non-histone proteins, and regulate cellular responses. Histone deacetylase inhibitors(HDAi) induce apoptosis and growth arrest of tumor cells, and are clinically used as anti-tumor drugs. Moreover, HDAi recently have been shown to have immune-regulatory and anti-inflammatory functions in vitro and in animal models.Rheumatoid arthritis is a chronic inflammation of joints, leading to the joint destruction. We have examined anti-rheumatic effects of HDAi on various types of cells and in an animal model. The in vitro effects of HDAi were as follows : 1) HDAi induced apoptosis in RA-SF, and synergized with anti-Fas Ab to induce cell death probably by down regulating FLIP expression. 2) Among 11 HDACs, HDAC1 expression was higher in RASF than in OASF by qPCR. 3) HDAi altered the phenotype of human peripheral blood monocyte-drived DC to express lower CD1 and produce reduced IL-12, resulting in less Th1 cells induction. 5) HDAi dramatically suppressed OC differentiation by suppressing NF-AT expression. The in vivo experiments proved that HDAi ameliorates arthritis in SKG mice by altering DC phenotype into regulatory one.Our data indicate that HDAi have multiple anti-inflammatory effects, suggesting that they can be used as a potential anti-inflammatory and immunosuppressive drug.