Inhibition of Interleukin 1β (IL-1β) Expression by Anthrax Lethal Toxin (LeTx) Is Reversed by Histone Deacetylase 8 (HDAC8) Inhibition in Murine Macrophages

Abstract

Many pathogenic microbes often release toxins that subvert the host's immune responses to render the environment suitable for their survival and proliferation. LeTx is one of the toxins causing immune paralysis by cleaving and inactivating the mitogen-activated protein kinase (MAPK) kinases (MEKs). Here, we show that inhibition of the histone deacetylase 8 (HDAC8) by either the HDAC8-specific inhibitor PCI-34051 or small interference (si)RNAs rendered LeTx-exposed murine macrophages responsive to LPS in pro-IL-1␤ production. HDAC8 selectively targeted acetylated histone H3 lysine 27 (H3K27Ac), which is known to associate with active enhancers. LeTx induced HDAC8 expression, in part through inhibiting p38 MAPK, which resulted in a decrease of H3K27Ac levels. Inhibition of HDAC8 increased H3K27Ac levels and enhanced NF-B-mediated pro-IL-1␤ enhancer and messenger RNA production in LeTx-exposed macrophages. Collectively, this study demonstrates a novel role of HDAC8 in LeTx immunotoxicity and regulation of pro-IL-1␤ production likely through eRNAs. Targeting HDAC8 could be a strategy for enhancing immune responses in macrophages exposed to LeTx or other toxins that inhibit MAPKs.

HDAC8 Prevents Anthrax Lethal Toxin-induced Cell Cycle Arrest through Silencing PTEN in Human Monocytic THP-1 Cells

“…We previously showed that LeTx or HDAC8 overexpression leads to H3K27Ac deacetylation in murine macrophages [22,28]. Since the levels of H3K27Ac and H3K27me3 are inversely correlated, and an increase of H3K27me3 leads to down-regulation of PTEN expression [29,30,31,32], we examined both acetylation and methylation levels of H3K27.…”

“…It is also known that H3K27 acetylation is mutually exclusive to methylation of the residue and H3K27 deacetylation is a prerequisite chromatin context for PRC2 to be active on histones [29,30,31]. In murine macrophages, we showed that LeTx suppresses gene transcription in part through up-regulating HDAC8 that leads to H3K27 deacetylation [23,28]. As expected, LeTx also induced HDAC8 mRNA expression, decreased H3K27Ac levels and increased H3K27me3 levels over 3 days in THP-1 cells.…”

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

“…Li et al reported that the HDAC8 inhibitor ITF3056 attenuated TNF-α and IL-1β production without a significant decrease in the IL-1β mRNA levels in vitro [ 27 ]. However, another study described that HDAC8 could suppress IL-1β production, leading to the hypoacetylation of histone H3K27 located on the pro-IL-1β enhancer and promoter regions in macrophages, such function that could be reversed by the HDAC8 inhibitor PCI-34051 to increase IL-1β production [ 49 ]. Consistently, the function of WK2-16 on IL-1β production is similar to PCI-34051.…”

HDAC8 Inhibition Reduces Lesional Iba-1+ Cell Infiltration after Spinal Cord Injury without Effects on Functional Recovery

“…There is a trend indicating increased Arg-1 expression after treatment with 10 µM PCI-34051, although, owing to high variation, this trend does not reach statistical significance. Previous studies have shown effects of PCI-34051 on mitochondrial cell death genes and IL-1β expression in lower concentrations (20 nM and 100 nM) on toxin-induced resistant RAW264.7 macrophages [ 43 , 44 ]. In addition, PCI-34051 was found to be neuroprotective in concentrations between 1 µM and 10 µM.…”