HDAC6 Deacetylase Activity Is Critical for Lipopolysaccharide-Induced Activation of Macrophages

Yan, Bing; Xie, Songbo; Zhu, Liu; Ran, Jie; Li, Yuanyuan; Wang, Jian; Yang, Yang; Zhou, Jun; Li, Dengwen; Liu, Min

doi:10.1371/journal.pone.0110718

Cited by 54 publications

(42 citation statements)

References 44 publications

(44 reference statements)

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“…Furthermore, HDAC6 inhibition leads to hyperacetylation of Hsp90, thereby suppressing the activity of Foxp3 + T regulatory cells 13, 14. Additionally, we have previously demonstrated that HDAC6 regulates lipopolysaccharide-induced macrophage activation in a deacetylase activity-dependent manner 15. In the present study, we have explored the role of HDAC6 in the regulation of IL-17 expression in T lymphocytes.…”

Section: Introductionmentioning

confidence: 84%

HDAC6 regulates IL-17 expression in T lymphocytes: implications for HDAC6-targeted therapies

Yan¹,

Liu²,

Hong³

et al. 2017

Theranostics

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The pro-inflammatory cytokine interleukin 17 (IL-17) is critically involved in immunity and inflammation. T-helper 17 and γδ T cells are the predominant sources of IL-17 in the immune system. However, the mechanisms by which the expression of IL-17 is regulated in T cells remain elusive. Here, we demonstrate that loss of histone deacetylase 6 (HDAC6) in mice does not affect the generation of CD4+ or CD8+ T cells, but stimulates the development of IL-17-producing γδ T cells. Our data further show that HDAC6 deficiency increases the production of IL-17 by Vγ4+ γδ T cells in the spleen and lymph nodes. Consistent with these observations, small-molecule inhibition of HDAC6 activity in γδ T cells promotes the expression of IL-17 in vitro. These data thus reveal that HDAC6 represses IL-17 production in T cells, providing novel insights into the role of HDAC6 in the immune system. These findings also have important implications for the clinical investigation of HDAC6-targeted therapies.

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Section: Introductionmentioning

confidence: 84%

HDAC6 regulates IL-17 expression in T lymphocytes: implications for HDAC6-targeted therapies

Yan¹,

Liu²,

Hong³

et al. 2017

Theranostics

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“…HDAC6 inhibition possesses anti-tumor and anti-inflammation effects [13–15]. HDAC6 has many endogenous substrates including chaperones and cytoskeletal proteins [16].…”

Section: Introductionmentioning

confidence: 99%

HDAC6 inhibition prevents TNF-α-induced caspase 3 activation in lung endothelial cell and maintains cell-cell junctions

et al. 2016

Oncotarget

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Pro-inflammatory mediators such as TNF-α induce caspase activation in endothelial cells, which leads to degradation of cellular proteins, induction of apoptotic signaling, and endothelial cell dysfunction. New therapeutic agents that can inhibit caspase activation may provide protection against inflammatory injury to endothelial cells. In the present study, we examined the effects of selective histone deacetylase 6 (HDAC6) inhibition on TNF-α induced caspase 3 activation and cell-cell junction dysfunction in lung endothelial cells. We also assessed the protective effects of HDAC6 inhibition against lung inflammatory injury in a mouse model of endotoxemia. We demonstrated that selective HDAC6 inhibition or knockdown of HDAC6 expression was able to prevent caspase 3 activation in lung endothelial cells and maintain lung endothelial cell-cell junctions. Mice pre-treated with HDAC6 inhibitors exhibited decreased endotoxin-induced caspase 3 activation and reduced lung vascular injury as indicated by the retention of cell-cell junction protein VE-Cadherin level and alleviated lung edema. Collectively, our data suggest that HDAC6 inhibition is a potent therapeutic strategy against inflammatory injury to endothelial cells.

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“…HDAC6 is predominantly present in the cytoplasm due to nuclear export signals (Bertos et al, ). HDAC6 has been implicated in the development of various human diseases, including cancers, neurological disorders, and inflammatory diseases (reviewed in Li et al, ; Vishwakarma et al, ), and functions in the regulation of pro‐ and anti‐inflammatory genes (Wang et al, ; Yan et al, ). Inhibition or knockdown of HDAC6 markedly enhances lipopolysaccharide (LPS)‐induced production of anti‐inflammatory IL‐10 by increasing p38 phosphorylation in macrophages (Wang et al, ).…”

Section: Introductionmentioning

confidence: 99%

HDAC6 mediates HIV‐1 tat‐induced proinflammatory responses by regulating MAPK‐NF‐kappaB/AP‐1 pathways in astrocytes

Youn

Choi

et al. 2015

Glia

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Human immunodeficiency virus (HIV)-1 transactivator of transcription (Tat) is a viral protein that induces extensive neuroinflammation by up-regulating proinflammatory mediators, including cytokines, chemokines, and adhesion molecules. Histone deacetylase 6 (HDAC6) has been implicated in the transcriptional regulation of inflammatory genes. In this study, we investigated the possible role of HDAC6 in HIV-1 Tat-induced up-regulation of proinflammatory mediators in astrocytes. HIV-1 Tat augmented HDAC6 expression, which was correlated with a reduction in acetylated α-tubulin in CRT-MG human astroglioma cells and primary mouse astrocytes. Knockdown and pharmacological inhibition of HDAC6 significantly inhibited HIV-1 Tat-induced expression of CCL2, CXCL8, and CXCL10 chemokines; adhesion molecules; and subsequent adhesion of monocytes to astrocytes. HDAC6 knockdown attenuated HIV-1 Tat-induced activation of mitogen-activated protein kinase species, including ERK, JNK, and p38. Furthermore, HDAC6 knockdown suppressed HIV-1 Tat-induced activation of NF-κB and AP-1. Thus, HDAC6 is involved in HIV-1 Tat-induced expression of proinflammatory genes by regulating mitogen-activated protein kinase-NF-κB/AP-1 pathways and serves as a molecular target for HIV-1 Tat-mediated neuroinflammation GLIA 2015;63:1953-1965.

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HDAC6 Deacetylase Activity Is Critical for Lipopolysaccharide-Induced Activation of Macrophages

Cited by 54 publications

References 44 publications

HDAC6 regulates IL-17 expression in T lymphocytes: implications for HDAC6-targeted therapies

HDAC6 regulates IL-17 expression in T lymphocytes: implications for HDAC6-targeted therapies

HDAC6 inhibition prevents TNF-α-induced caspase 3 activation in lung endothelial cell and maintains cell-cell junctions

HDAC6 mediates HIV‐1 tat‐induced proinflammatory responses by regulating MAPK‐NF‐kappaB/AP‐1 pathways in astrocytes

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