Sulforaphane epigenetically regulates innate immune responses of porcine monocyte-derived dendritic cells induced with lipopolysaccharide.

Xueqi Qu,Maren Pröll,Muhammad Jasim Uddin,Mehmet Ulas Cinar,Dawit Tesfaye,Dessie Salilew-Wondim,Ernst Tholen,Christine Große-Brinkhaus,Christiane Neuhoff,Michael Hölker,Karl Schellander,Rui Zhang,Christian Looft,Md Munir Hossain,Partha Mukhopadhyay

doi:10.1371/journal.pone.0121574

Xueqi Qu, Maren Pröll + Show 13 more

Open Access

https://doi.org/10.1371/journal.pone.0121574

Copy DOI

Abstract

Histone acetylation, regulated by histone deacetylases (HDACs) is a key epigenetic mechanism controlling gene expressions. Although dendritic cells (DCs) are playing pivotal roles in host immune responses, the effect of epigenetic modulation of DCs immune responses remains unknown. Sulforaphane (SFN) as a HDAC inhibitor has anti-inflammatory properties, which is used to investigate the epigenetic regulation of LPS-induced immune gene and HDAC family gene expressions in porcine monocyte-derived dendritic cells (moDCs). SFN was found to inhibit the lipopolysaccharide LPS induced HDAC6, HDAC10 and DNA methyltransferase (DNMT3a) gene expression, whereas up-regulated the expression of DNMT1 gene. Additionally, SFN was observed to inhibit the global HDAC activity, and suppressed moDCs differentiation from immature to mature DCs through down-regulating the CD40, CD80 and CD86 expression and led further to enhanced phagocytosis of moDCs. The SFN pre-treated of moDCs directly altered the LPS-induced TLR4 and MD2 gene expression and dynamically regulated the TLR4-induced activity of transcription factor NF-κB and TBP. SFN showed a protective role in LPS induced cell apoptosis through suppressing the IRF6 and TGF-ß1 production. SFN impaired the pro-inflammatory cytokine TNF-α and IL-1ß secretion into the cell culture supernatants that were induced in moDCs by LPS stimulation, whereas SFN increased the cellular-resident TNF-α accumulation. This study demonstrates that through the epigenetic mechanism the HDAC inhibitor SFN could modulate the LPS induced innate immune responses of porcine moDCs.

Highlights

Apart from pork production, pig has been used as a major mammalian model in several fields of medical research because of the anatomy, physiology, metabolism, organ development and disease progression similarities to other mammalian species [1]
The expression profiling of genes encoding the four classes of histone deacetylases (HDACs) were quantified by the qRT-PCR
While LPS stimulation altered the expression of five HDAC genes, six HDAC gene expressions remained non-significant in monocyte-derived dendritic cells (moDCs) in response to LPS stimulation (Fig. 1)

Summary

Introduction

Apart from pork production, pig has been used as a major mammalian model in several fields of medical research because of the anatomy, physiology, metabolism, organ development and disease progression similarities to other mammalian species [1]. The porcine DC has been frequently used as an experimental model for studying the disease progression and pathogenesis after a highly contagious viral or bacterial infection in either human or swine viral infection physiology [2,3,4,5,6]. Such kind of external environmental stimuli can modify the epigenetic profile. NF-κB plays an essential role in the regulation of transcription of genes related to rapid responses to stress and pathogens, as well as in the development and differentiation of immune cells (such as DCs and monocytes) [10]. Sulforaphane (SFN) has been found to regulate expressions of immune related gene [12,13,14,15]

Objectives

Methods

Results

Conclusion