Therapeutic effects and its mechanism of HDACi on Arthritis

组蛋白脱乙酰酶(HDACs)从组蛋白和非组蛋白的赖氨酸残基中去除乙酰基，调节细胞反应。组蛋白脱乙酰酶抑制物(HDAi)可诱导肿瘤细胞的凋亡和生长停滞，临床上用作抗肿瘤药物。此外，HDAI最近在体外和动物模型中被证明具有免疫调节和抗炎作用。类风湿性关节炎是一种慢性关节炎症，导致关节破坏。我们研究了HDAI在不同类型细胞和动物模型上的抗风湿作用。HDAi的体外作用如下：1)HDAi诱导RA-SF细胞凋亡，并与抗Fas抗体协同作用，可能通过下调FliP的表达而诱导细胞死亡。2)定量聚合酶链式反应显示11例HDAC中，RASF的HDAC1表达高于OASF。3)HDAi改变了人外周血单核细胞驱动的DC的表型，降低了CD1的表达，减少了IL-12的产生，导致Th1细胞的诱导减少。5)HDAi通过抑制NF-AT的表达，显著抑制OC的分化。体内实验证明，HDAi通过将DC表型转变为调节型来改善SKG小鼠的关节炎。我们的数据表明，HDAi具有多种抗炎作用，提示它们可以作为一种潜在的抗炎和免疫抑制药物。

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.