Search for Roles for histone deaoetylas in rheumatic dit.roases and development of new thraputic approaches through HDAC inhibition.

1.丁酸盐抑制人单核细胞来源的树突状细胞发育过程中的CD 1表达和IL-12产生树突状细胞（DCs）通过MHC和CD 1的抗原呈递以及形成免疫应答的细胞因子产生在免疫功能中起关键作用。在这里，我们报告丁酸，组蛋白去乙酰化酶抑制剂，对人单核细胞衍生的DC的影响。丁酸盐处理在DC的发展强烈抑制CD 1分子的表达，而它只轻微影响CD 80，CD 86和MHC分子。抑制施加在蛋白质和mRNA水平，也观察到在存在的全反式维甲酸，CD 1d诱导剂。此外，丁酸处理的DC表现出较低的IL-12和IL-6的产生，在同种异体混合淋巴细胞反应中诱导较少的Th 1细胞。我们的研究结果表明，组蛋白乙酰化参与调节免疫反应，通过调节DC的发展。因此，HDAC可能是 ...更多信息 免疫反应的靶点. (-)表没食子儿茶素-3-没食子酸酯（EGCG）抑制破骨细胞分化及对小鼠实验性关节炎的影响目的：研究表没食子儿茶素-3-没食子酸酯（EGCG）对小鼠破骨细胞分化及对实验性关节炎的影响。通过抗酒石酸酸性磷酸酶（TRAP）染色、骨吸收实验、蛋白质印迹和定量RT-PCR检测EGCG的作用。通过注射抗胶原蛋白的单克隆抗体的混合物在小鼠中诱导关节炎。从第0天到实验结束（第15天）每天腹膜内施用EGCG（20 μ g/g）。结果：EGCG可减少TRAP阳性多核细胞的生成，降低骨吸收活性，降低破骨细胞特异性基因表达，但不影响细胞活力。EGCG下调NFATc的表达，但不下调NFkB、c-Fos和c-Jun的表达，提示下调NFATc是EGCG作用的分子基础之一。此外，EGCG治疗改善了关节炎小鼠的临床和组织学评分（p<0.05）。结论：EGCG抑制破骨细胞的分化，在短期内改善小鼠实验性关节炎。它仍然是建立是否表没食子儿茶素没食子酸酯是有用的预防和治疗骨质疏松症和类风湿性关节炎。少

1. Butyrate inhibits CD1 expression and IL-12 production during human monocyte-derived dendritic cell developmentDendritic cells (DCs) play a key role in immune function through antigen presentation by MHC and CD1, as well as cytokine production that shapes the immune response. Here we report the effects of butyrate, a histone deacetylase inhibitor, on human monocyte-derived DCs. Butyrate treatment during DC development strongly suppressed the expression of CD1 molecules, whereas it only marginally affected CD80, CD86, and MHC molecules. The suppression was exerted at protein and mRNA levels and also observed in the presence of all trans retinoic acid, a CD1d inducer. Moreover butyrate-treated DCs showed lower production of IL-12 and IL-6 in response to lipopolysaccharides and induced less Th 1 cells in allogenic mixed lymphocyte reactions. Our results imply that histone acetylation is involved in regulating immune responses through regulating DC development. Thus HDAC may be one of th … More e targets for control ling the immune response.2. (-) -Epigallocatechin-3-Galate suppresses osteoclast differentiation and ameliorates experimental arthritis in miceObjective: To verify the effects of (-)-Epigallocatechin-3-Galate (EGCG) on osteoclast differentiation and on experimental arthritis in mice.Methods: Human osteoclasts were differentiated from peripheral blood monocytes. The effects of EGCG were examined by tartrate resistant acid phosphatase (TRAP) staining, bone resorption assay, western blot, and quantitative RT-PCR. Arthritis was induced in mice by injecting a cocktail of monoclonal antibodies against collagen. EGCG (20 g/g) was administered every day intraperitoneally from day 0 through the end of the experiments (day 15). Effects of EGCG were determined by joint swelling, as well as by histology and TRAP staining on day 15.Results: EGCG reduced generation of TRAP-positive multinucleated cells, bone resorption activity, and osteoclast-specific gene expression without affecting cell viability. EGCG down-regulated expression of NFATc, but not of NFkB, c-Fos and c-Jun, suggesting that down-regulation of NFATc is one of molecular bases of EGCG action. Additionally EGCG treatment ameliorated clinical and histological scores of arthritic mice (p<0.05). The in vivo effect of EGCG on osteoclast differentiation was not clear in this model probably because EGCG suppressed inflammation itself.Conclusion: EGCG suppressed osteoclast differentiation and ameliorated experimental arthritis in mice in the short term. It remains to be established whether EGCG is useful for the prevention and treatment of osteoporosis and rheumatoid arthritis. Less