Histone deacetylase isoforms regulate innate immune responses by deacetylating mitogen‐activated protein kinase phosphatase‐1

  title={Histone deacetylase isoforms regulate innate immune responses by deacetylating mitogen‐activated protein kinase phosphatase‐1},
  author={Youngtae Jeong and Ronghui Du and Xiaolei Zhu and Shasha Yin and Jian Wang and Hengmi Cui and Wangsen Cao and Charles J. Lowenstein},
  journal={Journal of Leukocyte Biology},
The MAPK pathway mediates TLR signaling during innate immune responses. We discovered previously that MKP‐1 is acetylated, enhancing its interaction with its MAPK substrates and deactivating TLR signaling. As HDACs modulate inflammation by deacetylating histone and nonhistone proteins, we hypothesized that HDACs may regulate LPS‐induced inflammation by deacetylating MKP‐1. We found that mouse macrophages expressed a subset of HDAC isoforms (HDAC1, HDAC2, and HDAC3), which all interacted with… 

Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism

It is found that in the absence of HDAC1, HDAC2 is up‐regulated and these increased levels are compensatory, suggesting that these two HDACs have redundancy in regulating the inflammatory response of microglia.

Inhibition of HDAC Enzymes Contributes to Differential Expression of Pro-Inflammatory Proteins in the TLR-4 Signaling Cascade

The results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions and show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches.

Inhibition of histone deacetylase 1 or 2 reduces microglia activation through a gene expression independent mechanism

This study has identified that selective HDAC inhibition with inhibitors apicidin, MS-275 or MI-192, or specific knockdown of HDAC1 or 2 using siRNA, suppresses the expression of cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in BV2 murine microglia activated with lipopolysaccharide (LPS).

Histone deacetylase inhibitors restore IL-10 expression in lipopolysaccharide-induced cell inflammation and reduce IL-1β and IL-6 production in breast silicone implant in C57BL/6J wild-type murine model.

The ability of selective HDAC3, HDAC6, and HDAC8 inhibitors to reduce host inflammation in silicone implants promoting a thickness reduction of peri-implant fibrous capsule, upregulating IL-10 expression, and reducing the production of both IL-1β and IL-6 is evidenced.

HDAC1/2‐mediated regulation of JNK and ERK phosphorylation in bovine mammary epithelial cells in response to TNF‐α

The combined data suggest thatHDAC1/2‐specific inhibitors may prove efficacious for the treatment of bovine mastitis and suggest that HDACs1 and 2 regulate inflammatory gene expression via canonical and noncanonical mechanisms.

Control of cytokine mRNA degradation by the histone deacetylase inhibitor ITF2357 in rheumatoid arthritis fibroblast-like synoviocytes: beyond transcriptional regulation

This study identifies that regulation of cytokine mRNA stability is a predominant mechanism underlying ITF2357 anti-inflammatory properties, occurring via regulation of TTP.

Molecular mechanisms of histone deacetylases in rheumatoid arthritis fibroblast-like synoviocytes

The studies presented in this thesis were designed with the intention to characterize the expression and activity of class I and class II histone deacetylases (HDACs) in rheumatoid arthritis (RA) synovial tissue and fibroblasts-like synoviocytes (FLS), and to identify the molecular and anti-inflammatory mechanisms of action of broad- and isoform-selective HDAC inhibitors ( HDACi).

The Novel HDAC8 Inhibitor WK2-16 Attenuates Lipopolysaccharide-Activated Matrix Metalloproteinase-9 Expression in Human Monocytic Cells and Improves Hypercytokinemia In Vivo

In vivo studies indicated that WK2-16 could reduce the serum levels of TNF-α and IL-6 in endotoxemic mice and suggested that HDAC8 inhibition might provide a novel therapeutic strategy of hypercytokinemia in sepsis.



Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling

The data suggest that acetylation of MKP-1 inhibits innate immune signaling, and this pathway may be an important therapeutic target in the treatment of inflammatory diseases.

Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression

This study provides the first evidence that a histone deacetylase is essential for unrestricted cell proliferation by repressing the expression of selective cell cycle inhibitors.

A role for histone deacetylase activity in HDAC1-mediated transcriptional repression.

Site-directed mutagenesis was used to identify residues required for the enzymatic and structural integrity of HDAC1 and any one of four conserved residues causes deleterious effects on deacetylase activity and a reduced ability to bind a TPX-affinity matrix.

Histone deacetylase 2–mediated deacetylation of the glucocorticoid receptor enables NF-κB suppression

Reduction of HDAC2 plays a critical role in glucocorticoid insensitivity in repressing NF-κB–mediated, but not GRE-mediated, gene expression and it is shown that overexpression ofHDAC2 in glucose-insensitive alveolar macrophages from patients with COPD is able to restore glucoc Corticoid sensitivity.

Glucocorticoid Receptor Recruitment of Histone Deacetylase 2 Inhibits Interleukin-1β-Induced Histone H4 Acetylation on Lysines 8 and 12

ABSTRACT We have investigated the ability of dexamethasone to regulate interleukin-1β (IL-1β)-induced gene expression, histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity. Low

Negative and Positive Regulation of Gene Expression by Mouse Histone Deacetylase1

This study reveals a regulatory cross talk between HDAC1 and HDAC2 and a novel function forHDAC1 as a transcriptional coactivator and a new set of genes found to require HDAC activity and recruitment of HDac1 for their transcriptional activation.

Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses

  • H. ChiS. Barry R. Flavell
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2006
It is demonstrated that mice deficient in MKP-1 attenuates the activities of p38 MAPK and JNK to regulate both pro- and anti-inflammatory cytokines in TLR signaling, which highlights the complex mechanisms by which the MAPKs regulate innate immunity.

Role for Histone Deacetylase 1 in Human Tumor Cell Proliferation

The data support the idea that a drug targeting specific HDACs could be highly beneficial in the treatment of cancer, and inactivation of HDAC1 affected the transcription of specific target genes involved in proliferation and apoptosis.

Histone Deacetylase 3 (HDAC3) and Other Class I HDACs Regulate Colon Cell Maturation and p21 Expression and Are Deregulated in Human Colon Cancer*

HDAC3 is identified as a gene deregulated in human colon cancer and as a novel regulator of colon cell maturation and p21 expression and it is suggested that the growth-inhibitory and apoptotic effects induced by HDAC inhibitors are probably mediated through the inhibition of multiple HDACs.