trichostatin-a and Lupus-Erythematosus--Systemic

We sought to determine if the histone deacetylase inhibitor (HDI), trichostatin A (TSA), would alter systemic lupus erythematosus (SLE) in NZB/W mice. Fourteen to sixteen-week-old female NZB/W F1 mice were given TSA (1.0mg/kg body weight (BW)) intraperitonealy (i.p.) daily, TSA (1.0mg/kg BW) i.p.+anti-CD25 (250mg/mouse) i.p. every third day, only anti-CD25 (250mg/mouse) i.p., DMSO or isotype IgG. Disease progression was assessed as they aged. Mice were sacrificed at 26 or 38 weeks of age, tissues collected and evaluated. At 36 weeks, TSA-treated animals had decreased anti-double stranded DNA (dsDNA) autoantibodies and decreased protein excretion compared to controls. Spleen size and the percentage of CD4+CD69+ cells were decreased, with an increase in CD4+CD25+ T cells in the TSA-treated mice. Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis of T cells showed a decrease in IL-6 production but an increase in TGF-beta1 and Foxp3 in the TSA-treated animals. Kidney analysis showed a decrease in IgG and C3 deposition, decrease in pathologic glomerular disease and renal MCP-1, MMP-9, and IL-6 mRNA expression. Anti-CD25-treated mice euthanized at 26 weeks of age showed decreased Foxp3+CD4+CD25+ T cells compared to TSA-treated mice. These data suggest TSA administration modulates lupus-like disease, in part, by increasing T regulatory cells.

Topics: Animals; Antibodies, Antinuclear; Autoimmunity; CD4 Antigens; Disease Models, Animal; Disease Progression; Female; Flow Cytometry; Histone Deacetylase Inhibitors; Hydroxamic Acids; Immunologic Factors; Interleukin-2 Receptor alpha Subunit; Kidney; Lupus Erythematosus, Systemic; Mice; Mice, Inbred NZB; Organ Size; T-Lymphocytes, Regulatory; Up-Regulation

Studies in human systemic lupus erythematosus (SLE) suggest a possible role for histone deacetylases (HDACs) in skewed gene expression and disease pathogenesis. We used the MRL-lpr/lpr murine model of lupus to demonstrate that HDACs play a key role in the heightened levels of both Th1 and Th2 cytokine expression that contribute to disease. The availability of specific HDAC inhibitors (HDIs) such as trichostatin A (TSA) and suberonylanilide hydroxamic acid (SAHA) permits the study of the role of HDACs in gene regulation. Our results indicate that HDIs downregulate IL-12, IFN-gamma, IL-6, and IL-10 mRNA and protein levels in MRL-lpr/lpr splenocytes. This effect on gene transcription is associated with an increased accumulation of acetylated histones H3 and H4 in total cellular chromatin. To elucidate the in vivo effects of TSA on lupuslike disease, we treated MRL-lpr/lpr mice with TSA (0.5 mg/kg/d) for 5 weeks. Compared with vehicle-treated control mice, TSA-treated mice exhibited a significant reduction in proteinuria, glomerulonephritis, and spleen weight. Taken together, these findings suggest that increased expression of HDACs leading to an altered state of histone acetylation may be of pathologic significance in MRL-lpr/lpr mice. In addition, TSA or other HDIs may have therapeutic benefit in the treatment of SLE.

Topics: Animals; Autoantibodies; Down-Regulation; Enzyme Inhibitors; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-6; Kidney; Lupus Erythematosus, Systemic; Mice; Mice, Inbred MRL lpr; RNA, Messenger; Vorinostat

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lupus Erythematosus, Systemic; Mice; Protein Synthesis Inhibitors; Species Specificity; Vorinostat

Trichostatin A (TSA) is a potent reversible inhibitor of histone deacetylase, and it has been reported to have variable effects on the expression of a number of genes. In this report, we show that TSA suppresses the expression of the T cell receptor zeta chain gene, whereas, it upregulates the expression if its homologous gene Fc(epsilon) receptor I gamma chain. These effects are associated with decreased intracytoplasmic-free calcium responses and altered tyrosine phosphorylation pattern of cytosolic proteins. Along with these effects, we report that TSA suppresses the expression of the interleukin-2 gene. The effects of TSA on human T cells are predominantly immunosuppressive and reminiscent of the signaling aberrations that have been described in patients with systemic lupus erythematosus.

Topics: Adolescent; Adult; Calcium Signaling; CD3 Complex; Cells, Cultured; Enzyme Inhibitors; Ephrin-A2; Gene Expression Regulation; Humans; Hydroxamic Acids; Immunosuppressive Agents; Interleukin-2; Lupus Erythematosus, Systemic; Membrane Proteins; Receptors, Antigen, T-Cell; Receptors, IgE; Signal Transduction; T-Lymphocytes; Time Factors; Tyrosine

In systemic lupus erythematosus (SLE), T helper cells exhibit increased and prolonged expression of cell-surface CD40 ligand (CD154), spontaneously overproduce interleukin-10 (IL-10), but underproduce interferon-gamma (IFN-gamma). We tested the hypothesis that the imbalance of these gene products reflects skewed expression of CD154, IL-10, and IFN-gamma genes. Here, we demonstrate that the histone deacetylase inhibitor, trichostatin A, significantly down-regulated CD154 and IL-10 and up-regulated IFN-gamma gene expression in SLE T cells. This reversal corrected the aberrant expression of these gene products, thereby enhancing IFN-gamma production and inhibiting IL-10 and CD154 expression. That trichostatin A can simultaneously reverse the skewed expression of multiple genes implicated in the immunopathogenesis of SLE suggests that this pharmacologic agent may be a candidate for the treatment of this autoimmune disease.

Topics: Adult; Base Sequence; CD40 Ligand; Cells, Cultured; DNA Primers; Female; Genes, Immunoglobulin; Humans; Hydroxamic Acids; Interferon-gamma; Interleukin-10; Lupus Erythematosus, Systemic; Male; RNA, Messenger; T-Lymphocytes