Activity and expression of histone acetylases and deacetylases in inflammatory phenotypes of asthma

Gunawardhana, Lakshitha; Gibson, Peter G.; Simpson, Jodie L.; Powell, Heather; Baines, Katherine J.

doi:10.1111/cea.12168

Cited by 57 publications

(50 citation statements)

References 43 publications

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“…Asthma is commonly associated with enhanced STAT6 and Ige gene expression that are linked to an increase in HAT activities and decrease in HDAC activities (Gunawardhana et al, 2014;Li et al, 2014). Consistent with these studies, our data confirmed the association of hyperacetylation of histone H3 with asthma (Fig.…”

Section: Acetylation Of H3k9 Associated With Asthma In Il-4/stat6 Patsupporting

confidence: 91%

Histone H3k9 and H3k27 Acetylation Regulates IL‐4/STAT6‐Mediated Igε Transcription in B Lymphocytes

Wang

Duan

et al. 2015

The Anatomical Record

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IL-4 activates STAT6 and causes the subsequent up-regulation of Ig heavy chain germline Ige via chromatin remodeling involved in B lymphocytes development. STAT6 acts as a molecular switch to regulate the higher-order chromatin remodeling via dynamically orchestrating co-activators (CBP/Tudor-SN) and co-repressors (HDAC1/PSF). Here, we demonstrated that STAT6/Tudor-SN/PSF form a complex, balancing the acetylation and deacetylation states to co-regulate IL-4/STAT6 gene transcription. In addition, we confirmed that IL-4 treatment increased the HATs activity in Ramos cells. As "active" markers, the expression of H3K9ac and H3K27ac increased after treatment with IL-4. However, transcriptional repressors such as H3K9me3 and H3K27me3 decreased in response to IL-4 stimulation. Moreover, IL-4 treatment enhanced H3 acetylation at the Ige promoter regions. Our results revealed that the Ige gene transcription is regulated by histone modifications in the IL-4/STAT6 pathway. The study will provide novel insights into the pathogenesis of allergic diseases.

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Section: Acetylation Of H3k9 Associated With Asthma In Il-4/stat6 Patsupporting

confidence: 91%

Histone H3k9 and H3k27 Acetylation Regulates IL‐4/STAT6‐Mediated Igε Transcription in B Lymphocytes

Wang

Duan

et al. 2015

The Anatomical Record

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“…Acetylation of histones by transcriptional coactivator HAT leads to chromatin opening for inflammatory gene transcription. It has been reported that the total HAT/HDAC activity ratio is elevated in lungs from severe asthmatics (29). In LPS/IFN-g-treated mouse lungs, we observed a significant increase in total HAT/HDAC activity ratio.…”

Section: Andrographolide Restores Steroid Sensitivity To Block Lps/ Isupporting

confidence: 57%

“…Intact HDAC2 function is indispensable in mediating the transrepression action of steroids to modulate transcriptional activity of NF-kB and AP-1 (22). Elevated HAT activity and impaired HDAC2 protein expression and activity have been reported in lung tissues, alveolar macrophages, and PBMCs from COPD and severe asthma patients (29,44,45). In the present study, we observed a major drop in nuclear HDAC2 level and total HDAC activity and an increase of the total HAT/HDAC activity ratio upon LPS/IFN-g stimulation, which might be responsible for LPS/IFN-g-induced steroid insensitivity.…”

Section: Discussionmentioning

confidence: 99%

Andrographolide Restores Steroid Sensitivity To Block Lipopolysaccharide/IFN-γ–Induced IL-27 and Airway Hyperresponsiveness in Mice

Liao

Tan

Wong

2016

The Journal of Immunology

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LPS and IFN-γ alone or in combination have been implicated in the development of steroid resistance. Combined LPS/IFN-γ strongly upregulates IL-27 production, which has been linked to steroid-resistant airway hyperresponsiveness (AHR). Andrographolide, a bioactive molecule isolated from the plant Andrographis paniculata, has demonstrated anti-inflammatory and antioxidant properties. The present study investigated whether andrographolide could restore steroid sensitivity to block LPS/IFN-γ–induced IL-27 production and AHR via its antioxidative property. The mouse macrophage cell line Raw 264.7, mouse primary lung monocytes/macrophages, and BALB/c mice were treated with LPS/IFN-γ, in the presence and absence of dexamethasone and/or andrographolide. Levels of IL-27 in vitro and in vivo were examined and mouse AHR was assessed. Dexamethasone alone failed to inhibit LPS/IFN-γ–induced IL-27 production and AHR in mice. Andrographolide significantly restored the suppressive effect of dexamethasone on LPS/IFN-γ–induced IL-27 mRNA and protein levels in the macrophage cell line and primary lung monocytes/macrophages, mouse bronchoalveolar lavage fluid and lung tissues, and AHR in mice. LPS/IFN-γ markedly reduced the nuclear level of histone deacetylase (HDAC)2, an essential epigenetic enzyme that mediates steroid anti-inflammatory action. LPS/IFN-γ also decreased total HDAC activity but increased the total histone acetyltransferase/HDAC activity ratio in mouse lungs. Andrographolide significantly restored nuclear HDAC2 protein levels and total HDAC activity, and it diminished the total histone acetyltransferase/HDAC activity ratio in mouse lungs exposed to LPS/IFN-γ, possibly via suppression of PI3K/Akt/HDAC2 phosphorylation, and upregulation of the antioxidant transcription factor NF erythroid-2–related factor 2 level and DNA binding activity. Our data suggest that andrographolide may have therapeutic value in resensitizing steroid action in respiratory disorders such as asthma.

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“…Another recent study found that in neutrophilic asthma, there was increased HAT and decreased HDAC activity in isolated PBMCs. However, there were no differences in the expression levels of the HATs p300, KAT2B, cAMP response element-binding protein-binding protein or the HDACs HDAC1, HDAC2 or HDAC3, which could indicate differences in activity due to post-translational effects [46]. More recently, it has been identified that acetylation of histone H3 lysine 18 (H3K18) is elevated in asthma epithelium compared with healthy subjects [47], which is in line with a shift toward increased HAT activity.…”

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confidence: 82%

Targeting Transcription Factor Lysine Acetylation in Inflammatory Airway Diseases

et al. 2017

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Asthma and chronic obstructive pulmonary disease are inflammatory airway diseases for which alternative therapeutic strategies are urgently needed. Interestingly, HDAC inhibitors show anti-inflammatory effects in mouse models for these diseases. Here we explore underlying mechanisms that may explain these effects. In previous studies, effects of HDAC inhibitors on histone acetylation are often correlated with their effects on gene expression. However, effects of HDAC inhibitors on transcription factors and their acetylation status may be particularly important in explaining these effects. These effects are also cell type-specific. Recent developments (including chemoproteomics and acetylomics) allow for a more detailed understanding of the selectivity of HDAC inhibitors, which will drive their further development into applications in inflammatory airway diseases. Asthma and chronic obstructive pulmonary disease (COPD) are common inflammatory airway diseases. These diseases affect millions of people world-wide, and globally, the incidence is increasing. For asthma, the clinical symptoms include among others wheezing and shortness of breath. COPD is characterized by shortness of breath upon exercise and a largely irreversible and progressive airflow limitation [1][2][3][4]. In asthma the larger airways are mainly affected, whereas in COPD, the lung parenchyma and peripheral airways are mainly affected [3]. The immunopathology of asthma and COPD is characterized by different types of inflammatory cells that are at play. For example, asthma is driven by T helper 2 (T h 2) cells, dendritic cells and is characterized by eosinophilic inflammation. In asthma there is mast-cell sensitization by immunoglobulin E (IgE), and multiple bronchoconstrictors are released [1,2]. On the other hand, COPD is characterized by T helper 1 (T h 1) cells, cytotoxic T cells and neutrophilic inflammation [5,3]. The inflammation in COPD is also characterized by increased numbers of macrophages, neutrophils and innate lymphoid cells recruited from the circulation. A variety of pro-inflammatory mediators, including cytokines, chemokines, growth factors and lipid mediators are secreted by these cell types [5]. Currently, glucocorticoids are the cornerstone in the treatment of asthma and COPD, however, this is not effective in all patients. Severe asthmatics display glucocorticoid resistance [6], and the effectivity of glucocorticoids in COPD patients is subject to debate [7,8]. Alternative therapeutic strategies are needed for these patients, which currently form a major health burden for society due to high socioeconomic costs [1][2][3][4]9]. Studying the underlying molecular mechanisms may enable the identification of new therapeutic targets. These underlying processes may include epigenetic regulation, such as lysine acetylation. Lysine acetylation is a post-translational modification of proteins, which is crucial in the regulation of cellular processes such as signal transduction and gene expression [10,11]. Lysine acetylation was initiall...

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Activity and expression of histone acetylases and deacetylases in inflammatory phenotypes of asthma

Abstract: Neutrophilic airway inflammation is associated with increased HAT and reduced HDAC activity in blood monocytes, demonstrating further systemic manifestations relating to the altered inflammatory gene transcription profile of neutrophilic asthma.

Cited by 57 publications

References 43 publications

Histone H3k9 and H3k27 Acetylation Regulates IL‐4/STAT6‐Mediated Igε Transcription in B Lymphocytes

Histone H3k9 and H3k27 Acetylation Regulates IL‐4/STAT6‐Mediated Igε Transcription in B Lymphocytes

Andrographolide Restores Steroid Sensitivity To Block Lipopolysaccharide/IFN-γ–Induced IL-27 and Airway Hyperresponsiveness in Mice

Targeting Transcription Factor Lysine Acetylation in Inflammatory Airway Diseases

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