| Abstract: |
Epigenetic regulation of gene expression is involved in the development of many diseases. Histone acetylation is a posttranslational modification of the nucleosomal histone tails that is regulated by the balance of histone deacetylases and histone acetyltransferases. Alterations in the balance of histone acetylation have been shown to cause aberrant expression of genes that are a hallmark of many diseases, including systemic lupus erythematosus. In this study, we determined whether suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor: 1) inhibits inflammatory mediator production in vitro and 2) modulates lupus progression in vivo. Mesangial cells isolated from 10-wk-old MRL/lpr mice were stimulated with LPS/IFN-γ and incubated with SAHA. TNF-α, IL-6, NO, and inducible NO synthase expression were inhibited by SAHA. We then treated MRL/lpr mice with daily injections of SAHA from age 10 to 20 wk. The animals treated with SAHA had decreased spleen size and a concomitant decrease in CD4-CD8- (double-negative) T cells compared with controls. Serum autoantibody levels and glomerular IgG and C3 deposition in SAHA-treated mice were similar to controls. In contrast, proteinuria and pathologic renal disease were significantly inhibited in the mice receiving SAHA. These data indicate that SAHA blocks mesangial cell inflammatory mediator production in vitro and disease progression in vivo in MRL/lpr mice. |
| Keywords: |
controlled study; disease course; nonhuman; t lymphocyte; antigens, cd3; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; animal tissue; cells, cultured; spleen; kidney disease; animal experiment; animal model; inflammation; inflammation mediators; cyclophosphamide; immunoglobulin enhancer binding protein; in vivo study; in vitro study; gene expression regulation; double stranded dna; tumor necrosis factor alpha; gamma interferon; immunoglobulin g; histone; disease progression; anti-inflammatory agents, non-steroidal; cd4-positive t-lymphocytes; interleukin 6; vorinostat; hydroxamic acids; lipopolysaccharide; systemic lupus erythematosus; antiinflammatory activity; adjuvants, immunologic; histocompatibility antigens class ii; autoantibody; organ size; histone deacetylases; proteinuria; autoantibodies; lymphopenia; immunosuppressive agents; histone deacetylase; acetylation; inducible nitric oxide synthase; mice, inbred mrl lpr; nitric oxide; lupus erythematosus, systemic; spleen size; antibody blood level; injections, intraperitoneal; histone acetyltransferase; complement component c3; glomerular mesangium; female; priority journal; article; dna antibody; mesangium cell
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