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

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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