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Histone Deacetylase Inhibitors Suppress the Expression of Inflammatory and Innate Immune Response Genes in Human Microglia and Astrocytes

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Abstract

Histone deacetylase inhibitors (HDACi) have been proposed as therapies for certain cancers and as an anti-reservoir therapy for HIV+ individuals with highly active anti-retroviral therapy, yet their roles in glial inflammatory and innate antiviral gene expression have not been defined. In this study, we examined the effects of two non-selective HDACi, trichostatin A and valproic acid, on antiviral and cytokine gene expression in primary human microglia and astrocytes stimulated with TLR3 or TLR4 ligand. HDACi potently suppressed the expression of innate antiviral molecules such as IFNβ, interferon-simulated genes, and proteins involved in TLR3/TLR4 signaling. HDACi also suppressed microglial and astrocytic cytokine and chemokine gene expression, but with different effects on different groups of cytokines. These results have important implications for the clinical use of HDACi.

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Abbreviations

HDAC:

Histone deacetylase

HDACi:

HDAC inhibitor

IFNAR:

Type I interferon receptor

ISRE:

IFN-stimulated response element

PIC (poly I:C):

Polyinosinic–polycytidylic acid

PBDA:

Porphobilinogen deaminase

Q-PCR:

Real-time RT–PCR

VA:

Valproic acid

IDO:

Indoleamine 2, 3-dioxygenase

IRF:

Interferon regulatory factor

ISGs:

IFN-stimulated genes

LPS:

Lipopolysaccharide

TLR:

Toll-like receptor

TRIF:

Toll/interleukin-1 receptor domain-containing adaptor protein inducing IFNβ

TSA:

Trichostatin A

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Acknowledgments

This study was supported by NIH RO1 MH55477, KO1 MH084705, Molecular Neuropathology Training grant NIH T32 NS007098, and Einstein CFAR grant P30 AI051519. We thank the Einstein Human Fetal Tissue Repository for the tissue and Meng-Liang Zhao for tissue culture.

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  1. Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Hyeon-Sook Suh, Shinyeop Choi, Pallavi Khattar, Namjong Choi & Sunhee C. Lee

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  1. Hyeon-Sook Suh
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  2. Shinyeop Choi
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Correspondence to Sunhee C. Lee.

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Suh, HS., Choi, S., Khattar, P. et al. Histone Deacetylase Inhibitors Suppress the Expression of Inflammatory and Innate Immune Response Genes in Human Microglia and Astrocytes. J Neuroimmune Pharmacol 5, 521–532 (2010). https://doi.org/10.1007/s11481-010-9192-0

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