Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. 1258 92

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-gamma and incubated with SAHA. TNF-alpha, 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.
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PMID:Modulation of renal disease in MRL/lpr mice by suberoylanilide hydroxamic acid. 1535 68

The baseline level of gene expression varies between healthy controls and systemic lupus erythematosus (SLE) patients, and among SLE patients themselves. These variations may explain the different clinical manifestations and severity of disease observed in SLE. Epigenetic mechanisms, which involve DNA and histone modifications, are predictably associated with distinct transcriptional states. To understand the interplay between various histone modifications, including acetylation and methylation, and lupus disease, we performed differential expression histone modification analysis in splenocytes from the MRL-lpr/lpr mouse model of lupus. Using stable isotope labeling in combination with mass spectrometry, we found global site-specific hypermethylation (except H3 K4 methylation) and hypoacetylation in histone H3 and H4 MRL-lpr/lpr mice compared to control MRL/MPJ mice. Moreover, we have identified novel histone modifications such as H3 K18 methylation, H4 K31 methylation, and H4 K31 acetylation that are differentially expressed in MRL-lpr/lpr mice compared to controls. Finally, in vivo administration of the histone deacetylase inhibitor trichostatin A (TSA) corrected the site-specific hypoacetylation states on H3 and H4 in MRL-lpr/lpr mice with improvement of disease phenotype. Thus, this study is the first to establish the association between aberrant histone codes and pathogenesis of autoimmune disease SLE. These aberrant post-translational histone modifications can therefore be reset with histone deacetylase inhibition in vivo.
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PMID:Resetting the epigenetic histone code in the MRL-lpr/lpr mouse model of lupus by histone deacetylase inhibition. 1633 48

Hydralazine was one of the first orally active antihypertensive drugs developed. Currently, it is used principally to treat pregnancy-associated hypertension. Hydralazine causes two types of side effects. The first type is an extension of the pharmacologic effect of the drug and includes headache, nausea, flushing, hypotension, palpitation, tachycardia, dizziness, and salt retention. The second type of side effects is caused by immunologic reactions, of which the drug-induced lupus-like syndrome is the most common, and provides clues to underscoring hydralazine's DNA demethylating property in connection with studies demonstrating the participation of DNA methylation disorders in immune diseases. Abnormalities in DNA methylation have long been associated with cancer. Despite the fact that malignant tumors show global DNA hypomethylation, regional hypermethylation as a means to silence tumor suppressor gene expression has attracted the greatest attention. Reversibility of methylation-induced gene silencing by pharmacologic means, which in turns leads to antitumor effects in experimental and clinical scenarios, has directed efforts toward developing clinically useful demethylating agents. Among these, the most widely used comprise the nucleosides 5-azacytidine and 2'deoxy-5-azacytidine; however, these agents, like current cytotoxic chemotherapy, causes myelosuppression among other side effects that could limit exploitation of their demethylating properties. Among non-nucleoside DNA demethylating drugs currently under development, the oral drug hydralazine possess the ability to reactivate tumor suppressor gene expression, which is silenced by promoter hypermethylation in vitro and in vivo. Decades of extensive hydralazine use for hypertensive disorders that demonstrated hydralazine's clinical safety and tolerability supported its testing in a phase I trial in patients with cancer, confirming its DNA demethylating activity. Hydralazine is currently being evaluated, along with histone deacetylase inhibitors either alone or as adjuncts to chemotherapy and radiation, for hematologic and solid tumors in phase II studies.
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PMID:Hydralazine target: from blood vessels to the epigenome. 1650

Major recent advances in the field of chromatin remodeling have dramatically changed our understanding of the ways in which genes are regulated. Epigenetic regulators such as histone deacetylases (HDACs) and histone acetyltransferases (HATs) are increasingly being implicated as direct or indirect components in the regulation of expression of neuronal, immune and other tissue specific genes. HDACs and HATs have been shown to play important roles in cell growth, cell cycle control, development, differentiation and survival. Mutations in genes that encode HDAC-binding proteins cause neurological disorders, such as MeCP2 mutations in Rett's syndrome. Mutations of CBP, a gene with HAT function, cause the mental retardation-associated Rubinstein-Taybi syndrome. Recently, HDAC inhibitors have been found to ameliorate progression of the spinal muscular atrophy (SMA) motor neuron disease and the Huntington disease mouse models. The neuroprotective role of HDAC inhibitors seems to extend to other diseases that share mechanisms of oxidative stress, inflammation and neuronal cell apoptosis. HDAC inhibitors also have widespread modulatory effects on gene expression within the immune system and have been used successfully in the lupus and rheumatoid arthritis autoimmune disease models. Recently, we demonstrated the efficacy of the HDAC inhibitor Trichostatin A in ameliorating disease in the multiple sclerosis (MS) animal model, experimental autoimmune encephalomyelitis (EAE). In this review we describe the current literature surrounding these inhibitors and propose a rationale for harnessing both their neuroprotective and anti-inflammatory effects to treat MS, an autoimmune, demyelinating and degenerative disease of the human central nervous system (CNS).
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PMID:Rationale for the use of histone deacetylase inhibitors as a dual therapeutic modality in multiple sclerosis. 1799 7

Dynamic changes in chromatin structure through ATP-dependent remodeling and covalent modifications on histones play important roles in transcription regulation. Among the many chromatin modifiers identified, the NuRD (nucleosome remodeling histone deacetylase) complex is unique because it possesses both nucleosome remodeling and histone deacetylase activities. To understand the biological function of the NuRD complex, we generated a knock-out mouse model of the Mta2 (metastasis-associated protein 2) gene, which encodes a NuRD-specific component. Mta2 null mice exhibited partial embryonic lethality. The surviving mice developed lupus-like autoimmune symptoms including skin lesions, bodyweight loss, glomerulonephritis, liver inflammation, and production of autoantibodies. Transplantation of bone marrow cells from Mta2 null mice recapitulated some of the symptoms including skin lesion and bodyweight loss in the recipient mice. Mta2 null T lymphocytes showed normal development but hyperproliferation upon stimulation, which correlates with hyperinduction of interleukin (IL)-2, IL-4, and interferon (IFN)-gamma. T cell hyperproliferation, but not other autoimmune symptoms, was observed in T cell-specific Mta2 knock-out mice. Mta2 null T cells produced more IL-4 and IFN-gamma under Th2 activation conditions, but normal levels of IL-4 and IFN-gamma under Th1 activation conditions. Furthermore, we found that IL-4 is a direct target gene of Mta2. Our study suggests that Mta2/NuRD is involved in modulating IL-4 and IFN-gamma expression in T cell immune responses, and gene expression in non-T cells plays an important role in controlling autoimmunity.
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PMID:Inactivation of NuRD component Mta2 causes abnormal T cell activation and lupus-like autoimmune disease in mice. 1835 70

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.
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PMID:The histone deacetylase inhibitor trichostatin A upregulates regulatory T cells and modulates autoimmunity in NZB/W F1 mice. 1865 65

Several lines of evidence suggest the involvement of disturbance in epigenetic processes in autoimmune disease. Most noteworthy is the global DNA hypomethylation seen in lupus. Epigenetic states in difference from genetic lesions are potentially reversible and hence candidates for pharmacological intervention. Potential targets for drug development are histone modification and DNA methylating and demethylating enzymes. The most advanced set of drugs in clinical development are histone deacetylase (HDAC) inhibitors. However, the prevalence of DNA hypomethylation in lupus suggests that we should shift our attention from HDAC inhibitors to DNA demethylation inhibitors. MBD2 was recently proposed to be involved in demethylation in T cells in lupus and is, therefore, a candidate target. Although this field is at its infancy, it carries great promise.
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PMID:Epigenetic therapeutics in autoimmune disease. 1964 76

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterized by the dysfunction of T cells, B cells, and dendritic cells and by the production of antinuclear autoantibodies. This editorial provides a synopsis of newly discovered genetic factors and signaling pathways in lupus pathogenesis that are documented in 11 state-of-the-art reviews and original articles. Mitochondrial hyperpolarization underlies mitochondrial dysfunction, depletion of ATP, oxidative stress, abnormal activation, and death signal processing in lupus T cells. The mammalian target of rapamycin, which is a sensor of the mitochondrial transmembrane potential, has been successfully targeted for treatment of SLE with rapamycin or sirolimus in both patients and animal models. Inhibition of oxidative stress, nitric oxide production, expression of endogenous retroviral and repetitive elements such as HRES-1, the long interspersed nuclear elements 1, Trex1, interferon alpha (IFN-alpha), toll-like receptors 7 and 9 (TLR-7/9), high-mobility group B1 protein, extracellular signal-regulated kinase, DNA methyl transferase 1, histone deacetylase, spleen tyrosine kinase, proteasome function, lysosome function, endosome recycling, actin cytoskeleton formation, the nuclear factor kappa B pathway, and activation of cytotoxic T cells showed efficacy in animal models of lupus. Although B cell depletion and blockade of anti-DNA antibodies and T-B cell interaction have shown success in animal models, human studies are currently ongoing to establish the value of several target molecules for treatment of patients with lupus. Ongoing oxidative stress and inflammation lead to accelerated atherosclerosis that emerged as a significant cause of mortality in SLE.
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PMID:Pathogenic mechanisms in systemic lupus erythematosus. 2001 60

In systemic lupus erythematosus (SLE), T lymphocytes overexpress CD70 (TNFSF7 gene), leading to the synthesis of autoreactive IgGs. CD70 upregulation in SLE CD4(+) T cells is associated with hypomethylation of TNFSF7 promoter. In this study, we explored histone modifications in the TNFSF7 promoter region in SLE CD4(+) T cells, and characterized the effects of a DNA methyltransferase inhibitor (5-azaC) and a histone deacetylase inhibitor (TSA) on CD70 expression. We found that CD70 mRNA was significantly increased in active lupus CD4(+) T cells, and in control cells treated with 5-azaC, TSA, or both. Histone H3 acetylation and dimethylated H3 lysine 4 (H3K4me2) levels were significantly elevated in patients with lupus, and both factors correlated positively with disease activity. MeCP2 protein levels within the TNFSF7 promoter decreased in patients with active lupus. Treatment of CD4+ T cells with 5-azaC alone significantly raised H3K4 dimethyl levels at the TNFSF7 locus. TSA treatment significantly increased H3 and H4 acetylation levels, as well as levels of H3K4 dimethylation at the TNFSF7 locus. Treatment with 5-azaC plus TSA enhanced H3 acetylation levels. These findings indicate that aberrant histone modifications within the TNFSF7 promoter may contribute to the development of lupus by increasing CD70 expression in CD4(+) T cells.
Lupus 2011 Nov
PMID:Histone modifications and methyl-CpG-binding domain protein levels at the TNFSF7 (CD70) promoter in SLE CD4+ T cells. 2186 61


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