Class I and II histone deacetylase inhibition by ITF2357 reduces SLE pathogenesis in vivo

Regna, Nicole L.; Chafin, Cristen B.; Hammond, Sarah; Puthiyaveetil, Abdul Gafoor; Caudell, David L.; Reilly, Christopher M.

doi:10.1016/j.clim.2014.01.002

Cited by 67 publications

(42 citation statements)

References 61 publications

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“…To determine the level of HDAC6 activity in BM, splenic, and glomerular cells from MRL/lpr and C57BL/6 mice, HDAC6 protein was immunoprecipitated as previously published[28]. The immunoprecipitated protein was normalized using the Bradford protein assay then subjected to the HDAC activity assay.…”

Section: Methodsmentioning

confidence: 99%

HDAC expression and activity is upregulated in diseased lupus-prone mice

Regna

Vieson

Gojmerac

et al. 2015

International Immunopharmacology

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Prior studies have shown that pan-HDAC inhibition can decrease disease in lupus mice; however, the mechanisms(s) remain to be elucidated. MRL/MpJ-Faslpr (MRL/lpr) mice develop a lupus-like disease characterized by anti-dsDNA production, lymphoproliferation, and immune complex-mediated glomerulonephritis. Early- and late-disease (12 and 20 weeks-of-age respectively) female MRL/lpr mice were compared to age-matched, healthy C57BL/6 mice for HDAC expression and activity in bone marrow (BM) B cells, splenic B and T cells, and glomerular cells. We found that HDAC6 was significantly overexpressed in B cells, splenic T cells and glomerular cells, whereas HDAC9 expression was significantly increased in splenic T cells, BM B cells and glomerular cells. Due to the overexpression of HDAC6, we tested whether treatment with a selective HDAC6 inhibitor (ACY-738) or a pan-HDAC inhibitor (TsA) would decrease HDAC activity. ACY-738 significantly reduced cytoplasmic HDAC activity whereas TsA significantly decreased both nuclear and cytoplasmic HDAC activity. In vitro studies in mesangial cells showed that ACY-738 increased α-tubulin and Hsp90 acetylation resulting in decreased nuclear activation of NF-κB. Treatment of pre-B cells with ACY-738 decreased the Bcl-2:Bax ratio leading to a pro-apoptotic environment. These results suggest that increased HDAC6 expression and activity contribute to SLE pathogenesis, and isoform-selective HDAC inhibitors may prove beneficial in the treatment of SLE by acetylating key signaling and transcription factors in inflammation and cell activation.

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Section: Methodsmentioning

confidence: 99%

HDAC expression and activity is upregulated in diseased lupus-prone mice

Regna

Vieson

Gojmerac

et al. 2015

International Immunopharmacology

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“…Treatment with ITF2357 decreased the IL17 level and increased the percentage of Treg cells through elevating FOXP3 acetylation [Regna et al, 2014]. An increased number of Treg cells may reduce autoantibody production [Regna et al, 2014]. Given the improvement in the similar diseases mentioned above, ITF2357 may have a therapeutic benefit in SLE.…”

Section: Drugs Targeting the Major Components Of The Epigenetic Mechamentioning

confidence: 99%

“…ITF2357 is a hydroxamic acid-derived compound, which is a specific class I and II HDAC inhibitor. Treatment with ITF2357 decreased the IL17 level and increased the percentage of Treg cells through elevating FOXP3 acetylation [Regna et al, 2014]. An increased number of Treg cells may reduce autoantibody production [Regna et al, 2014].…”

Section: Drugs Targeting the Major Components Of The Epigenetic Mechamentioning

confidence: 99%

Aberrant Epigenetic Regulation in the Pathogenesis of Systemic Lupus Erythematosus and Its Implication in Precision Medicine

Zhan

Guo²,

Lu³

2016

Cytogenet Genome Res

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Great progress has been made in the last decades in understanding the complex immune dysregulation in systemic lupus erythematosus (SLE), yet the efforts to pursue an effective treatment of SLE proved to be futile. The pathoetiology of SLE involves extremely complicated and multifactorial interaction among various genetic and epigenetic factors. Multiple gene loci predispose to disease susceptibility, and the interaction with epigenetic modifications mediated through sex, hormones, and the hypothalamo-pituitary-adrenal axis complicates susceptibility and manifestations of this disease. Finally, certain environmental and psychological factors probably trigger the disease via epigenetic mechanisms. In this review, we summarize and discuss recent epigenetic studies of SLE and suggest a personalized approach to the dissection of disease onset and therapy or precision medicine. We speculate that in the future, precision medicine based on epigenetic and genetic information could help guide more effective targeted therapeutic intervention.

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“…The inhibition of histone deacetylase can upregulate B-cell microRNAs (miRNAs) that silence AICDA/Aicda (AID) and PRDM1/Prdm1 (Blimp-1), contributing to B-cell differentiation processes that underpin antibody and autoantibody responses in lupus MRL/Faslpr/lpr mice (32). HDAC inhibitors are also able to ameliorate renal lesions in lupus nephritis (LN) (33). A clinical study also showed that mycophenolic acid could upregulate the level of histone H3/H4 global acetylation by regulating HATs and HDACs in lupus CD4 + T cells and affected the histone H4 acetylation and histone H3K4 tri-methylation levels in the CD40L promoter region that inhibited the expression of CD40L, which indicates the potential epigenetic mechanism of therapeutic effects in SLE (34).…”

Section: Histone Modifications and Slementioning

confidence: 99%

Epigenetics in systemic lupus erythematosus

Xiao

Zuo

2015

Biomedical Reports

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Abstract. Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, with mechanisms that remain to be elucidated. Previous studies have proposed that genes and environments are required for lupus to develop and flare. It has been found that epigenetics have a significant influence on SLE. The present review will concentrate on epigenetics in SLE. There are a number of studies reporting that autoreactive T cells and B cells in patients with SLE have evidence of altered patterns of DNA methylation, modifications of histones and microRNA (miRNA). Long noncoding RNAs (lncRNAs) are another type of noncoding RNAs, which have an important role in epigenetics. lncRNAs may possibly become a new hotspot in SLE.

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Class I and II histone deacetylase inhibition by ITF2357 reduces SLE pathogenesis in vivo

Cited by 67 publications

References 61 publications

HDAC expression and activity is upregulated in diseased lupus-prone mice

HDAC expression and activity is upregulated in diseased lupus-prone mice

Aberrant Epigenetic Regulation in the Pathogenesis of Systemic Lupus Erythematosus and Its Implication in Precision Medicine

Epigenetics in systemic lupus erythematosus

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